Inhibition of Microglial CD40 Expression by Pituitary Adenylate Cyclase-activating Polypeptide is Mediated by Interleukin-10

Journal of Neuroimmunology. May, 2002  |  Pubmed ID: 12020953

Microglia are intrinsic mediators of the central nervous system (CNS) immune response induced by a variety of insults. Activated microglia express costimulatory molecules CD40 and B7 that are important equally for T-cell activation and further activation of microglia. In this study, we sought to investigate the regulation of costimulatory molecule expression on primary microglia and microglial cell line, BV-2, by pituitary adenylyl cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), potent anti-inflammatory neuropeptides. The neuropeptides inhibited CD40 and B7-2 mRNA expression in activated microglia. PACAP decreased surface expression of CD40 and B7-2 on activated microglia. The inclusion of an anti-IL-10 antibody completely abrogated PACAP inhibition of lipopolysaccharide (LPS)-induced CD40 expression, suggesting that PACAP inhibition is at least in part mediated by IL-10. Indeed, PACAP enhanced LPS-induced IL-10 mRNA and protein levels in microglia. These data indicate that PACAP, through an increase in IL-10 protein, can down-regulate important costimulatory molecule expression on microglia, thereby possibly affecting CNS immunity.

Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) As Modulators of Both Innate and Adaptive Immunity

Critical Reviews in Oral Biology and Medicine : an Official Publication of the American Association of Oral Biologists. 2002  |  Pubmed ID: 12090463

The structurally related neuropeptides VIP and PACAP are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulate the production of the anti-inflammatory cytokine IL-10. These events are mediated through the VIP/PACAP effects on de novo expression or nuclear translocation of several transcription factors, i.e., NFkappaB, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFkappaB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model.

Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Inhibit Chemokine Production in Activated Microglia

Glia. Aug, 2002  |  Pubmed ID: 12112366

Microglia react to even minor disturbances in CNS homeostasis and function as critical regulators of CNS inflammation. Activated microglia secrete inflammatory mediators such as cytokines and chemokines, which contribute to the pathophysiological changes associated with several neuroimmunologic disorders. Microglia-derived inflammatory chemokines recruit various populations of immune cells, which initiate and maintain the inflammatory response against foreign antigens. Entry and retention of activated immune cells in the CNS is a common denominator in a variety of traumatic, ischemic, and degenerative diseases. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two structurally related neuropeptides that function as potent anti-inflammatory factors in the periphery. Here we investigated the effects of VIP and PACAP on chemokine production by activated microglia. VIP and PACAP inhibit the expression of the microglia-derived CXC chemokines MIP-2 and KC, and of the CC chemokines MIP-1alpha, -1beta, MCP-1, and RANTES. The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP/PACAP on NFkB binding. The VIP/PACAP inhibition of both chemokine production and of NFkB binding is mediated through the specific receptor VPAC1 and involves a cAMP-dependent intracellular pathway. Of biological significance is the fact that the inhibition of chemokine production by VIP/PACAP leads to a significant reduction in the chemotactic activity generated by activated microglia for peripheral leukocytes, i.e., neutrophils, macrophages, and lymphocytes. Because reduction in the number and activation of infiltrating leukocytes represents an important factor in the control of inflammation in the CNS, VIP and/or PACAP released by neurons during an inflammatory response could serve as neuronal survival factors by limiting the inflammatory process.

Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Promote in Vivo Generation of Memory Th2 Cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Nov, 2002  |  Pubmed ID: 12223451

Functionally active effector T cells are generated through clonal expansion. Most effector T cells are later eliminated, whereas a small number survive and differentiate into memory T cells. The mechanisms by which some effector T cells escape apoptosis and become memory T cells are not understood. Neuropeptides such as the vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit antigen-induced apoptosis of CD4 T cells. By using an in vivo long-term experimental model, in which CD4 T cells from TRC-transgenic mice were transferred into hosts, we demonstrate that VIP and PACAP induce the survival and/or generation of antigen-specific CD4 T cells with a memory Th2 phenotype. This was confirmed by the fact that transgenic CD4 T cells were recovered only from mice that received Th2, but not Th1 effector cells, in the presence of VIP or PACAP. In vitro, VIP/PACAP support the survival of Th2, but not Th1, cell lines through an inhibition of antigen-induced apoptosis. The role of neuropeptides in the biased development of Th2 memory cells is particularly relevant in view of the immune deviation existing in immune-privileged sites such as the brain and eye, where Th2, but not Th1, responses occur in nonpathological conditions.

Vasoactive Intestinal Peptide (VIP) Inhibits the Proliferation of Bone Marrow Progenitors Through the VPAC1 Receptor

Experimental Hematology. Sep, 2002  |  Pubmed ID: 12225791

The cellular and molecular mechanisms of hematopoietic stimulation have been studied. However, an understanding of negative effects in the hematopoietic system remains elusive. To this end, we studied the effects of vasoactive intestinal peptide (VIP) on bone marrow (BM) progenitors.

VIP and PACAP Down-regulate CXCL10 (IP-10) and Up-regulate CCL22 (MDC) in Spleen Cells

Journal of Neuroimmunology. Dec, 2002  |  Pubmed ID: 12446011

The immunoregulatory neuropeptides VIP and PACAP favor Th2-type immune responses. Antigen-stimulated Th2 cells produce VIP, VIP/PACAP induce Th2 cytokine responses, and promote the preferential survival of Th2 effectors. In this study, we investigate the effects of VIP/PACAP on two chemokines, i.e. CXCL10 (IP-10) acting on CXCR3 expressed on activated Th1 cells, and CCL22 (MDC) acting on CCR4 and 8 expressed on activated Th2 cells. VIP and PACAP down-regulate CXCL10, and up-regulate CCL22 in vivo and in vitro. The effects on the two chemokines appear to be different in mechanistic terms. The fact that VIP/PACAP might promote the directed migration of Th2 cells adds a new dimension to their participation in the Th2 auto-regulatory loop.

Galanin Down-regulates Microglial Tumor Necrosis Factor-alpha Production by a Post-transcriptional Mechanism

Journal of Neuroimmunology. Jan, 2003  |  Pubmed ID: 12507772

The neuropeptide galanin (GAL) is up-regulated following neuronal axotomy or inflammation. Since other neuropeptides act as immunomodulatory agents, we sought to determine whether GAL might affect the murine microglial cell line BV2, which expresses the GAL2 receptor. Even at very low concentrations, GAL inhibited tumor necrosis factor-alpha (TNF alpha) release but not TNF alpha mRNA levels in LPS-stimulated BV2 cells. Northern blot analysis showed that GAL inhibited the addition of a poly(A) tail, and stability assays showed that it also destabilized TNF alpha mRNA. Thus, GAL inhibits TNF alpha production by a post-transcriptional mechanism that both prevents the efficient addition of the poly(A) tail and accelerates TNF alpha mRNA degradation.

Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Inhibit the Production of Inflammatory Mediators by Activated Microglia

Journal of Leukocyte Biology. Jan, 2003  |  Pubmed ID: 12525573

Microglia play a central role in the regulation of immune and inflammatory activities, as well as tissue remodeling in the central nervous system. However, activation of microglia is a histopathological hallmark of several neurodegenerative diseases. Pathological microglial activation is believed to contribute to progressive damage in neurodegenerative diseases through the release of proinflammatory and/or cytotoxic factors, including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-12, and nitric oxide (NO). Hence, it is important to unravel mechanisms regulating microglia activation of inflamed brain parenchyma to provide insights into efficient therapeutic intervention. This study examines the role of two anti-inflammatory neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) on the production of various proinflammatory factors by endotoxin-stimulated microglia. VIP and PACAP inhibit TNF-alpha, IL-1beta, IL-6, and NO production by lipopolysaccharide (LPS)-activated microglia. The specific type 1 VIP receptor mediates the inhibitory effect of VIP/PACAP, and cyclic adenosine monophosphate is the major, second messenger involved. VIP and PACAP regulate the production of these proinflammatory factors at a transcriptional level by inhibiting p65 nuclear translocation and nuclear factor-kappaB-DNA binding. This effect is mediated, as neuropeptides stabilize the inhibitor IkappaB by inhibiting LPS-induced IkappaB-kinase activity. Therefore, the inhibitory effects on the production of proinflammatory mediators define VIP and PACAP as "microglia-deactivating factors" with significant, therapeutical potential for inflammatory/degenerative brain disorders.

Vasoactive Intestinal Peptide Inhibits IL-8 Production in Human Monocytes

Biochemical and Biophysical Research Communications. Feb, 2003  |  Pubmed ID: 12589787

Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, acts as a potent anti-inflammatory agent that inhibits the function of activated macrophages. VIP was shown to inhibit IL-6, TNFalpha, IL-12, chemokine, and nitric oxide production in endotoxin-activated macrophages. The present study reports the effect of VIP on IL-8 production by stimulated human monocytes. VIP inhibits IL-8 production in a dose- and time-dependent manner at the mRNA level. The specific VPAC1 receptor mediates the inhibitory effect of VIP. Two transduction pathways appear to be involved, a major cAMP-independent pathway and a secondary cAMP-dependent pathway. Of obvious physiological significance is the fact that VIP, presumably through the inhibition of IL-8 production, dramatically reduces the monocyte-induced neutrophil chemotaxis, an important event in the pathogenesis of several inflammatory and autoimmune disorders. These findings support the proposed role of VIP as a key endogenous anti-inflammatory agent and describe a novel mechanism, i.e., the inhibition of the production of monocyte-derived IL-8.

Vasoactive Intestinal Peptide Inhibits IL-8 Production in Human Monocytes by Downregulating Nuclear Factor KappaB-dependent Transcriptional Activity

Biochemical and Biophysical Research Communications. Mar, 2003  |  Pubmed ID: 12604342

Although interleukin-8 (IL-8) is a chemokine that plays a beneficial and central role in the inflammatory response, hematopoiesis, and angiogenesis, excessive IL-8 production can be deleterious to the host, and its selective inhibition represents an important therapeutic goal. Vasoactive intestinal peptide (VIP) is a neuropeptide that acts as a potent anti-inflammatory agent inhibiting the function of activated macrophages/monocytes. The present study reports the effect of VIP on IL-8 production by stimulated human THP1 monocytes. VIP inhibits IL-8 production in a dose- and time-dependent manner at the mRNA level. VIP seems to act by inhibiting the NF-kappaB-dependent IL-8 gene activation. The specific VPAC1 receptor mediates the inhibitory effect of VIP. Two transduction pathways appear to be involved, a major cAMP-independent pathway that preferentially blocks nuclear translocation of NF-kappaB and its binding to the kappaB site of the IL-8 promoter, and a cAMP-dependent pathway that inhibits the activation and binding to the IL-8 promoter of both CREB-binding protein (CBP) and TATA box-binding protein (TBP), two transcriptional cofactors strictly required for the transactivating activity of NF-kappaB. These findings support the proposed role of VIP as a key endogenous anti-inflammatory agent and describe a novel mechanism, i.e., the inhibition of the production of monocyte-derived IL-8, and are of obvious physiological significance, because VIP, through the inhibition of IL-8 production, could reduce the monocyte-induced neutrophil chemotaxis/infiltration, an important event in the pathogenesis of several inflammatory and autoimmune disorders.

Neuroprotective Effect of Vasoactive Intestinal Peptide (VIP) in a Mouse Model of Parkinson's Disease by Blocking Microglial Activation

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. May, 2003  |  Pubmed ID: 12626429

Parkinson's disease (PD) is a common neurodegenerative disorder with no effective protective treatment, characterized by a massive degeneration of dopaminergic neurons in the substantia nigra (SNpc) and the subsequent loss of their projecting nerve fibers in the striatum. To elucidate PD pathogenic factors, and thus to develop therapeutic strategies, a murine PD model based on the administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used extensively. It has been demonstrated that activated microglia cells actively participate in the pathogenesis of MPTP-induced PD through the release of cytotoxic factors. Because current treatments for PD are not effective, considerable research focused lately on a number of regulatory molecules termed microglia-deactivating factors. Vasoactive intestinal peptide (VIP), a neuropeptide with a potent anti-inflammatory effect, has been found to be protective in several inflammatory disorders. This study investigates the putative protective effect of VIP in the MPTP model for PD. VIP treatment significantly decreases MPTP-induced dopaminergic neuronal loss in SNpc and nigrostriatal nerve-fiber loss. VIP prevents MPTP-induced activation of microglia in SNpc and striatum and the expression of the cytotoxic mediators, iNOS, interleukin 1beta, and numor necrosis factor alpha. VIP emerges as a potential valuable neuroprotective agent for the treatment of pathologic conditions in the central nervous system, such as PD, where inflammation-induced neurodegeneration occurs.

The Neuropeptides VIP/PACAP and T Cells: Inhibitors or Activators?

Current Pharmaceutical Design. 2003  |  Pubmed ID: 12678866

The structurally related neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the expression at both mRNA and protein level of pro-inflammatory cytokines and chemokines, through effects on de novo expression or nuclear translocation of a number of transcription factors, i.e. NFkB, CREB, c-Jun, JunB, and IRF-1. In addition, VIP and PACAP promote Th2-type, and inhibit Th1-type responses in vivo and in vitro, through several mechanisms, including preferential survival of Th2 effectors and subsequent generation of Th2 memory cells. The function of VIP/PACAP as "macrophage deactivating factors" appears to be responsible for their protective effect in vivo in models of septic shock. Both deactivation of macrophages and inhibition of Th1-type responses appear to be responsible for the beneficial effect of VIP/PACAP in models of Th1-type autoimmune diseases such as rheumatoid arthritis.

PACAP in Immunity and Inflammation

Annals of the New York Academy of Sciences. May, 2003  |  Pubmed ID: 12794054

The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the VIP/secretin/glucagon family of peptides, produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, PACAP has been clearly identified as a potent anti-inflammatory factor that exerts its function by regulating the production of both anti- and proinflammatory mediators. In this sense, PACAP prevents death by septic shock, an acute inflammatory disease with a high mortality. In addition, PACAP regulates the expression of costimulatory molecules, inasmuch as this related to the modulation in the shift from Th1 towards Th2 differentiation. We recently reported that PACAP prevents the deleterious effects of arthritis by downregulating both inflammatory and autoimmune components of the disease. Therefore, PACAP and analogs have been proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn's disease, or autoimmune diabetes.

Vasoactive Intestinal Peptide Prevents Activated Microglia-induced Neurodegeneration Under Inflammatory Conditions: Potential Therapeutic Role in Brain Trauma

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Oct, 2003  |  Pubmed ID: 12923064

In most neurodegenerative disorders, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated microglia and its cytotoxic agents play a crucial pathologic role. Because current treatments for these diseases are not effective, several regulatory molecules termed "microglia-deactivating factors" recently have been the focus of considerable research. Vasoactive intestinal peptide (VIP) is a neuropeptide with a potent anti-inflammatory effect, which has been found to protect from other inflammatory disorders, such as endotoxic shock and rheumatoid arthritis. In the present study, we investigate the effect of VIP on inflammation-mediated neurodegeneration in vitro and in vivo as well as on the putative neuroprotective effect of VIP on experimental pathological conditions in which central nervous system (CNS) inflammation is involved, such as brain trauma. The involvement of activated microglia and their derived cytotoxic products is also studied. VIP has a clear neuroprotective effect on inflammatory conditions by inhibiting the production of microglia-derived proinflammatory factors (tumor necrosis factor alpha, interleukin-1beta, nitric oxide). In this sense, VIP prevents neuronal cell death following brain trauma by reducing the inflammatory response of neighboring microglia. Therefore, VIP emerges as a valuable neuroprotective agent for the treatment of pathologic conditions of the CNS where inflammation-induced neurodegeneration occurs.

Prostaglandin E2 Inhibits Production of the Inflammatory Chemokines CCL3 and CCL4 in Dendritic Cells

Journal of Leukocyte Biology. Nov, 2003  |  Pubmed ID: 12960284

Dendritic cells bridge innate and adaptive immunity and participate in both responses. Upon capture of pathogens, dendritic cells release inflammatory cytokines and chemokines, attracting other immune cells to the infection site. Anti-inflammatory cytokines, glucocorticoids, anti-inflammatory neuropeptides, and lipid mediators such as prostaglandin E2 (PGE2) limit and control the inflammatory response. In this study we report that exogenous PGE2 inhibits CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) expression and release from dendritic cells stimulated with either lipopolysaccharide (LPS), a TLR4 ligand, or peptidoglycan, a TLR2 ligand. The inhibition is dose-dependent and occurs at both the mRNA and protein levels. The inhibitory effect is mediated through EP2 and EP4 receptors and requires the presence of PGE2 at the time of LPS stimulation. Intraperitoneal administration of PGE2 together with LPS results in a reduction in the levels of CCL3 and CCL4 released in the peritoneal fluid, a reduction in the number of dendritic cells accumulating in the peritoneal cavity, and a reduction in CCL3 amount per cell in the peritoneal cell population. These results suggest that one of the mechanisms by which endogenous PGE2 acts as an anti-inflammatory agent, is the inhibition of inflammatory chemokine release from activated dendritic cells, preventing the excess accumulation of activated immune cells.

Acute Down-regulation of Antibody Production Following Spinal Cord Injury: Role of Systemic Catecholamines

Journal of Neuropathology and Experimental Neurology. Aug, 2003  |  Pubmed ID: 14503640

We investigated whether antibody production to antigens arising in the subarachnoid space is depressed acutely after spinal cord injury (SCI), and whether such depression is due to abnormal catecholamine levels. To assess antibody responses, ovalbumin (OVA) was injected into the spinal subarachnoid space (i.t.) of rats via an indwelling catheter after SCI at T4 or laminectomy (LAM). Antibody responses tested at days 0, 7, and 14 (d0, d7, d14) postinjury revealed that SCI animals exhibited an antibody response significantly lower than LAM animals on d7, but one that reached control levels by d14. ELISPOT assays indicated that the cervical lymph nodes, known to be innervated by superior cervical ganglia (SCG), processed i.t. OVA. The reduction in antibody production after SCI could not be mimicked with surgical deafferentation of the SCG. However, blockade of beta-adrenergic receptors prior to SCI did reverse the decrease, suggesting an adverse effect of the surge of catecholamines that accompanies the injury. Surgical removal of sympathetic inputs to the cervical lymph nodes prior to SCI failed to reverse the effect on antibody production, suggesting a systemic source of catecholamines. We conclude that antibody responses against i.t. antigens are attenuated acutely after SCI due to the massive release of systemic catecholamines that accompanies SCI.

Prostaglandin E2 Inhibits TNF Production in Murine Bone Marrow-derived Dendritic Cells

Cellular Immunology. Jun, 2003  |  Pubmed ID: 14527510

Exposure to pathogens induces dendritic cells to release inflammatory cytokines and chemokines. The inflammatory response is controlled by endogenous agents such as anti-inflammatory cytokines, glucocorticoids, anti-inflammatory neuropeptides, and lipid mediators. This study is the first report on the inhibition by prostaglandin E2 (PGE2) of TNF release from bone marrow-derived dendritic cells stimulated with lipopolysaccharide (LPS), a TLR4 ligand, or peptidoglycan, a TLR2 ligand. The inhibition of TNF occurs at both mRNA and protein level. The inhibitory effect of PGE2 is mediated by the EP2 and EP4 receptors, and involves both PKA signaling and mediation by DC-derived IL-10. Intraperitoneal administration of PGE2 together with LPS results in a reduction in serum TNF and intracellular TNF in peritoneal exudate cells, compared to LPS alone. In addition, administration of PGE2 in vivo reduces the numbers of CD11c+ DCc that accumulate in the peritoneal cavity in response to LPS. The various implications of the PGE2-induced reduction in TNF are discussed.

VIP/PACAP Oppositely Affects Immature and Mature Dendritic Cell Expression of CD80/CD86 and the Stimulatory Activity for CD4(+) T Cells

Journal of Leukocyte Biology. Jun, 2004  |  Pubmed ID: 15020654

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) released within lymphoid organs from nerve terminals and/or immune cells play a significant, anti-inflammatory role by inhibiting macrophage-induced inflammatory reactions and promoting T helper cell type 2 (Th2) responses. However, dendritic cells (DC) and not macrophages often are the major antigen-presenting cells and link between innate and adaptive immunity. The role of VIP/PACAP in DC development and function is mostly unknown. Here, we report that bone marrow-derived DC express VIP/PACAP receptors and that VIP and PACAP exert a differential effect on immature DC (iDC) and lipopolysaccharide (LPS)-treated DC. In iDC, VIP/PACAP up-regulates CD86 expression and enables them to stimulate T cell proliferation and differentiation into Th2 effectors in vivo and in vitro. In contrast, VIP/PACAP down-regulates CD80/CD86 expression in LPS-stimulated DC and strongly reduces their capacity to stimulate T cell proliferation and secretion of Th1 and Th2 cytokines. The VIP/PACAP effects on iDC and LPS-stimulated DC are mediated primarily through the VIP receptor 1. These results indicate that neuropeptides such as VIP and PACAP can differentially affect the function of iDC and mature DC. In the absence of an ongoing immune response, VIP/PACAP contributes to the initiation of Th2-type immunity, whereas in the presence of a full-blown, inflammatory reaction, VIP/PACAP act as anti-inflammatory agents.

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

Pharmacological Reviews. Jun, 2004  |  Pubmed ID: 15169929

First identified by Said and Mutt some 30 years ago, the vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator peptide. Subsequently, its biochemistry was elucidated, and within the 1st decade, their signature features as a neuropeptide became consolidated. It did not take long for these insights to permeate the field of immunology, out of which surprising new attributes for VIP were found in the last years. VIP is rapidly transforming into something more than a mere hormone. In evolving scientifically from a hormone to a novel agent for modifying immune function and possibly a cytokine-like molecule, VIP research has engaged many physiologists, molecular biologists, biochemists, endocrinologists, and pharmacologists and it is a paradigm to explore mutual interactions between neural and neuroendocrine links in health and disease. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as exciting new candidates for therapeutic intervention and drug development.

Prostaglandin E2 Induces IL-23 Production in Bone Marrow-derived Dendritic Cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Aug, 2004  |  Pubmed ID: 15180965

Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL-17 secretion from activated CD4+ T cells, and stimulating the proliferation of memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known immunomodulator, on the production of IL-23 by bone marrow- derived dendritic cells (BM-DCs). Our results indicate that PGE2 increases the production of functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2 induces both the expression of p19 and p40, without affecting p35 expression. The effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL-23 inducing activity of PGE2 in a synergistic manner. Recent studies described both pro- and anti-inflammatory effects of PGE2, and our results suggest an additional mechanism for its pro-inflammatory role, particularly significant for autoimmune diseases, such as rheumatoid arthritis.

VIP/PACAP Preferentially Attract Th2 Effectors Through Differential Regulation of Chemokine Production by Dendritic Cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Sep, 2004  |  Pubmed ID: 15231725

The neuropeptides vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) are potent immunomodulatory agents, acting as general anti-inflammatory factors. VIP, produced and secreted by Th2 cells following antigen stimulation, participates in a Th2 autoregulatory loop, promoting Th2-type responses through several nonexcluding mechanisms. VIP and PACAP affect the differentiation of CD4+ T cells directly and indirectly through antigen-presenting cells and promote the proliferation and/or survival of the Th2 effectors. Th1 and Th2 effectors express different chemokine receptors that control migration in response to various chemokines. In this study, we investigated the effects of VIP/PACAP on the production of CXCL10 (a Th1 chemokine) and of CCL22 (a Th2 chemokine) by bone marrow-derived dendritic cells. We found that VIP and PACAP inhibit CXCL10, while promoting CCL22 production, and that the effects are mediated through the VPAC1 receptor and involve cAMP/PKA as intracellular messengers. The induction of CCL22 and the suppression of CXCL10 in VIP/PACAP-treated dendritic cells results in the preferential chemoattraction of Th2 effectors both in vivo and in vitro. This is in agreement with the general Th2 bias induced by the two neuropeptides and adds an important parameter to their immunomodulatory function. By promoting Th2 migration, and preventing or reducing Th1 infiltration in inflammatory foci and sites of antigen presentation, VIP and PACAP help in resolving acute inflammatory processes and contribute to the prevention of chronic inflammation.

A Novel Signaling Pathway Mediates the Inhibition of CCL3/4 Expression by Prostaglandin E2

The Journal of Biological Chemistry. Dec, 2004  |  Pubmed ID: 15498767

In response to pathogen-associated molecular patterns, dendritic cells initiate an innate immune response characterized by expression and release of proinflammatory cytokines and chemokines. The extent of the inflammatory response is limited by various endogenous factors, including lipid mediators such as prostaglandin E(2) (PGE(2)). We described previously the inhibitory effect of PGE(2) on the expression and release of the inflammatory chemokines CCL3 and CCL4 from activated dendritic cells. In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor. The direct link between CDP and CCL3/4 transcription was established in knock-down experiments using CDP small interference RNA.

Prostaglandin E2 Promotes the Survival of Bone Marrow-derived Dendritic Cells

Journal of Immunology (Baltimore, Md. : 1950). Dec, 2004  |  Pubmed ID: 15557192

Since dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE(2), an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE(2) as a DC survival factor. Our studies demonstrate that PGE(2) protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE(2) release are highly susceptible to apoptosis and exogenous PGE(2) re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K --> Akt pathway. PGE(2) leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE(2) leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE(2) receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE(2) acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE(2) agonists to increase the survival of Ag-loaded DC following in vivo administration.

Vasoactive Intestinal Peptide Induces Regulatory Dendritic Cells with Therapeutic Effects on Autoimmune Disorders

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2005  |  Pubmed ID: 16150720

The induction of antigen-specific tolerance is critical for the prevention of autoimmunity and maintenance of immune tolerance. In addition to their classical role as sentinels of the immune response-inducing T cell reactivity, dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Tr). The possibility to generate tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Therefore, the characterization of the endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. In this study, we report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide, as a new approach to induce tolerogenic DCs with capacity to generate Tr cells, to restore tolerance in vivo, and to reduce the progression of rheumatoid arthritis and experimental autoimmune encephalomyelitis.

Vasoactive Intestinal Peptide Generates CD4+CD25+ Regulatory T Cells in Vivo

Journal of Leukocyte Biology. Dec, 2005  |  Pubmed ID: 16204628

CD4+CD25+ regulatory T (Treg) cells control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral expansion of CD4+CD25+ Treg cells. Although hormones such as estrogen and alpha-melanocyte-stimulating hormone have been recently reported to expand the CD4+CD25+ Foxp3-expressing Treg cell compartment, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+CD25+ Treg cells. In this study, we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg cells in vivo. The administration of VIP together with specific antigen to T cell receptor (TCR)-transgenic (Tg) mice results in the expansion of the CD4+CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. In addition to the increase in the number of CD4+CD25+ Treg cells, VIP induces more efficient suppressors on a per-cell basis. The VIP-generated CD4+CD25+ Treg cells transfer suppression, inhibit delayed-type hypersensitivity in TCR-Tg hosts, and prevent graft-versus-host disease in irradiated hosts reconstituted with allogeneic bone marrow.

The Neuropeptide Vasoactive Intestinal Peptide Generates Tolerogenic Dendritic Cells

Journal of Immunology (Baltimore, Md. : 1950). Dec, 2005  |  Pubmed ID: 16301637

Tolerogenic dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Treg). Endogenous factors contribute to the functional development of tolerogenic DCs. In this report, we present evidence that two known immunosuppressive neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), contribute to the development of bone marrow-derived tolerogenic DCs in vitro and in vivo. The VIP/PACAP-generated DCs are CD11c(low)CD45RB(high), do not up-regulate CD80, CD86, and CD40 following LPS stimulation, and secrete high amounts of IL-10. The induction of tolerogenic DCs is mediated through the VPAC1 receptor and protein kinase A, and correlates with the inhibition of IkappaB phosphorylation and of NF-kappaBp65 nuclear translocation. The VIP/PACAP-generated DCs induce functional Treg in vitro and in vivo. The VIP/DC-induced Treg resemble the previously described Tr1 in terms of phenotype and cytokine profile, suppress primarily Th1 responses including delayed-type hypersensitivity, and transfer suppression to naive hosts. The effect of VIP/PACAP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly in anatomical sites which exhibit immune deviation or privilege.

Granzyme B, a New Player in Activation-induced Cell Death, is Down-regulated by Vasoactive Intestinal Peptide in Th2 but Not Th1 Effectors

Journal of Immunology (Baltimore, Md. : 1950). Jan, 2006  |  Pubmed ID: 16365400

Following antigenic stimulation and differentiation, Th1 and Th2 effector cells contribute differently to cellular and humoral immunity. Vasoactive intestinal peptide (VIP) induces Th2 responses by promoting Th2 differentiation and survival. In this study, we investigate the mechanisms for the protective effect of VIP against activation-induced cell death (AICD) of Th2 effectors. Surprisingly, microarray and protein data indicate that VIP prevents the up-regulation of granzyme B (GrB) in Th2 but not Th1 effectors. This is the first report of GrB expression in Th cells and of its involvement in activation-induced apoptosis. The enhanced responsiveness of Th2 cells to VIP is probably due to the higher expression of VIP receptors. The effect of VIP on Th2 survival and GrB expression is mediated through the VIP receptors 1 and 2 and cAMP signaling through exchange protein activated by cAMP and, to a lesser degree, protein kinase A. In addition to effects on GrB, VIP also down-regulates Fas ligand (FasL) and perforin (Pfr) expression. The extrinsic Fas/FasL pathway and the intrinsic GrB-dependent pathway act independently in inducing AICD. The mechanisms by which GrB induces cell death in Th1/Th2 effectors include both fratricide and suicide. Fratricide killing, prevalent in wild-type cells, is calcium and Pfr dependent, whereas the cell death of Pfr-deficient Th cells involves Fas and GrB but is calcium independent. This study identifies GrB as a new significant player in Th1/Th2 AICD and characterizes two mechanisms for the protective effect of VIP on Th2 survival, i.e., the down-regulation of GrB and FasL expression.

Vasoactive Intestinal Peptide Generates Human Tolerogenic Dendritic Cells That Induce CD4 and CD8 Regulatory T Cells

Blood. May, 2006  |  Pubmed ID: 16397128

Induction of antigen-specific tolerance is critical for autoimmunity prevention and immune tolerance maintenance. In addition to their classical role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (T(reg)) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. We here report that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces the generation of human tolerogenic DCs with the capacity to generate CD4 and CD8 T(reg) cells from their respective naive subsets. The presence of VIP during the early stages of DC differentiation from blood monocytes generates a population of IL-10-producing DCs unable to fully mature after the effects of inflammatory stimuli. CD4 T(reg) cells generated with VIP-differentiated DCs resemble the previously described Tr1 cells in terms of phenotype and cytokine profile. CD8 T(reg) cells generated with tolerogenic VIP DCs have increased numbers of IL-10-producing CD8(+)CD28(-)-CTLA4(+) T cells. CD4 and CD8 T(reg) cells primarily suppress antigen-specific T(H)1-mediated responses. Therefore, the possibility of generating or expanding ex vivo tolerogenic DC(VIPs) opens new therapeutic perspectives for treating autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.

Vasoactive Intestinal Peptide Induces Regulatory T Cells During Experimental Autoimmune Encephalomyelitis

European Journal of Immunology. Feb, 2006  |  Pubmed ID: 16402407

CD4(+)CD25(+) regulatory T cells (Treg) control the immune response to a variety of antigens, including self-antigens. Several models support the idea of the peripheral generation of CD4(+)CD25(+) Treg from CD4(+)CD25(-) T cells. Little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4(+)CD25(+) Treg. In this study we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg in vivo during the development of experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. The administration of VIP to EAE mice results in the expansion of the CD4(+)CD25(+), Foxp3-expressing T cells in the periphery and the nervous system, which inhibit encephalitogenic T cell activation. In addition to the increase in the number of CD4(+)CD25(+) Treg, VIP induces more efficient suppressors on a per cell basis. The VIP-generated CD4(+)CD25(+) Treg transfer suppression and significantly ameliorate the progression of the disease.

Vasoactive Intestinal Peptide Induces Regulatory Dendritic Cells That Prevent Acute Graft-versus-host Disease While Maintaining the Graft-versus-tumor Response

Blood. May, 2006  |  Pubmed ID: 16418327

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) that induce the generation/activation of regulatory T (Tr) cells for the treatment of acute GVHD following allogeneic BMT has been recently established. Therefore, the identification of factors that contribute to the development of tolerogenic DCs is highly relevant. We report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide (VIP), as a new approach to induce tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated in the presence of VIP impair allogeneic haplotype-specific responses of donor CD4(+) cells in mice given transplants by inducing the generation of Tr cells in the graft. VIP-induced tolerogenic DCs did not abrogate the graft-versus-leukemia response presumably by not affecting the cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DCs in future therapeutic regimens may minimize the dependence on nonspecific immunosuppressive drugs used currently as antirejection therapy, and facilitate the successful transplantation from mismatched donors, by reducing the deleterious consequences of acute GVHD and extending the applicability of BMT.

Cortistatin, an Antiinflammatory Peptide with Therapeutic Action in Inflammatory Bowel Disease

Proceedings of the National Academy of Sciences of the United States of America. Mar, 2006  |  Pubmed ID: 16537513

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by, and binding to, immune cells. Crohn's disease is a chronic debilitating disease characterized by severe T helper 1 (Th1)-driven inflammation of the gastrointestinal tract. The aim of this study is to investigate the therapeutic effect of cortistatin in a murine model of colitis. Cortistatin treatment significantly ameliorated the clinical and histopathologic severity of the inflammatory colitis, abrogating body weight loss, diarrhea, and inflammation and increased the survival rate of the colitic mice. The therapeutic effect was associated with down-regulation of inflammatory and Th1-driven autoimmune response, including the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect was demonstrated. Importantly, cortistatin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. This work identifies cortistatin as an antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, cortistatin represents a multistep therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.

Therapeutic Effect of Vasoactive Intestinal Peptide on Experimental Autoimmune Encephalomyelitis: Down-regulation of Inflammatory and Autoimmune Responses

The American Journal of Pathology. Apr, 2006  |  Pubmed ID: 16565493

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system. Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a possible new strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP), a well-known immunosuppressive neuropeptide. Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), in a MS-related rodent model system. VIP suppressed EAE neuropathology by reducing central nervous system inflammation, including the regulation of a wide spectrum of inflammatory mediators, and by selectively blocking encephalitogenic T-cell reactivity. Importantly, VIP treatment was therapeutically effective in established EAE and prevented the recurrence of the disease. Consequently, VIP represents a novel multistep therapeutic approach for the future treatment of human MS.

Vasoactive Intestinal Peptide Generates CD4+CD25+ Regulatory T Cells in Vivo: Therapeutic Applications in Autoimmunity and Transplantation

Annals of the New York Academy of Sciences. Jul, 2006  |  Pubmed ID: 16888164

CD4+ CD25+ regulatory T cells (Treg) control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral generation of CD4+ CD25+ Treg from CD4+ CD25- T cells. However, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+ CD25+ Treg. We have found that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces functional Treg in vivo. The administration of VIP together with specific antigen to TCR-transgenic mice results in the expansion of the CD4+ CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. The VIP-generated CD4+ CD25+ Treg transfer suppression, inhibiting delayed-type hypersensitivity in the hosts, prevent graft-versus-host disease in irradiated host reconstituted with allogeneic bone marrow, and significantly ameliorate the clinical score in the collagen-induced arthritis model for rheumatoid arthritis and in the experimental autoimmune encephalomyelitis model for multiple sclerosis.

Vasoactive Intestinal Polypeptide Induces Regulatory Dendritic Cells That Prevent Acute Graft Versus Host Disease and Leukemia Relapse After Bone Marrow Transplantation

Annals of the New York Academy of Sciences. Jul, 2006  |  Pubmed ID: 16888171

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) with potent immunoregulatory properties by inducing the generation/activation of regulatory T cells (Tr) for the treatment of acute GVHD following allogeneic BMT has been recently established. Here we report the use of the known immunosuppressive neuropeptide, vasoactive intestinal polypeptide (VIP), as a new approach to inducing tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated with VIP impair allogeneic haplotype-specific responses of donor CD4+ T cells in transplanted mice by inducing the generation of Tr in the graft. Importantly, VIP-induced tolerogenic DCs did not abrogate the graft versus leukemia response, probably because they do not abrogate cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DC in future therapeutic regimens may facilitate the successful transplantation from mismatched donors, reducing the deleterious consequences of acute GVHD, extending the applicability of BMT.

Vasoactive Intestinal Peptide: the Dendritic Cell --> Regulatory T Cell Axis

Annals of the New York Academy of Sciences. Jul, 2006  |  Pubmed ID: 16888172

Tolerogenic dendritic cells (tDCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Treg). Endogenous factors contribute to the functional development of tDCs. In this article, we present evidence that two known immunosuppressive neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), contribute to the development of bone marrow-derived tDCs. The VIP/PACAP-generated DCs are CD11clowCD45RBhigh, do not upregulate CD80, CD86, and CD40 following lipopolysaccharide (LPS) stimulation, and secrete high amounts of IL-10. The VIP/PACAP-generated DCs induce functional Treg in vitro and in vivo. VIP/DCs induce antigen-specific tolerance in vivo, suppress delayed-type hypersensitivity (DTH), and T cells from VIP/DC-inoculated mice transfer the suppression to naïve hosts. The effect of VIP/PACAP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly in anatomical sites that exhibit immune deviation or privilege.

VIP Prevents Experimental Multiple Sclerosis by Downregulating Both Inflammatory and Autoimmune Components of the Disease

Annals of the New York Academy of Sciences. Jul, 2006  |  Pubmed ID: 16888178

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system (CNS). Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a new possible strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), an MS-related rodent model. VIP suppressed EAE neuropathology by reducing CNS inflammation and by selective blocking encephalitogenic T-cell reactivity, emerging as an attractive candidate for the treatment of human MS.

VIP Protects Th2 Cells by Downregulating Granzyme B Expression

Annals of the New York Academy of Sciences. Jul, 2006  |  Pubmed ID: 16888222

Selective differentiation of Th1/Th2 effectors contributes to cell- or antibody-mediated immunity. Vasoactive intestinal peptide (VIP) induces Th2 responses by promoting Th2 differentiation and survival. Here we investigate the mechanisms of VIP-induced Th2 survival. Microarray and protein data indicate that VIP prevents the upregulation of granzyme B (GrB) in Th2, but not Th1 effectors. This is the first report of GrB expression and of its involvement in activation-induced apoptosis of T helper cells. The enhanced responsiveness of Th2 cells to VIP is probably due to the higher expression of VIP receptors and alternative signaling pathways. This study identifies GrB as a new significant player in Th1/Th2 activation-induced cell death, and characterizes the mechanisms for the protective effect of VIP on Th2 survival.

A Novel Mechanism for Immunosuppression: from Neuropeptides to Regulatory T Cells

Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology. Dec, 2006  |  Pubmed ID: 18040812

Vasoactive intestinal peptide (VIP), a well-known immunoregulatory neuropeptide, affects both innate and adaptive immunity, and acts as a major anti-inflammatory factor in animal models of autoimmune diseases. VIP down-regulates the innate immune response by inhibiting the release of proinflammatory cytokines, chemokines, and nitric oxide by activated macrophages, microglia, and dendritic cells. VIP affects the adaptive immune response by reducing the costimulatory capacity of antigen-presenting cells, and by preferentially inducing Th(2)-type responses. This is accomplished through preferential Th(2) differentiation, enhanced survival of Th(2) effectors, and the induction of Th(2)-attracting chemokines. Recently, we discovered a novel mechanism for the immunosuppressive effect of VIP that involves the generation of antigen-specific regulatory T cells (Treg) through the induction of tolerogenic dendritic cells (tDC). In this work, we review the VIP-induced Treg generation both in vivo and in vitro, and the use of VIP-generated Treg in two models of autoimmunity, i.e., collagen-induced arthritis and experimental autoimmune encephalomyelitis, and in bone marrow transplantation as related to graft-versus-host disease and the graft-versus-leukemia response.

A Novel VIP Signaling Pathway in T Cells CAMP-->protein Tyrosine Phosphatase (SHP-2?)-->JAK2/STAT4-->Th1 Differentiation

Peptides. Sep, 2007  |  Pubmed ID: 17462790

Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent. In addition to the deactivation of macrophages, dendritic cells, and microglia, VIP shifts the Th1/Th2 balance, promoting the preferential differentiation and survival of Th2 cells, to the detriment of the proinflammatory Th1 effectors. Several mechanisms operate in the Th1/Th2 shift induced by VIP. Here we report on a novel mechanism for the effect of VIP on T cell differentiation, and show that VIP inhibits Th1 differentiation by interfering directly with the IL-12Jak2/STAT4 signaling pathway in T cells. The effect of VIP is cAMP-dependent, and appears to be mediated through the activation of protein tyrosine phosphatases (PTP), with SHP-2 as a potential target. The activation of PTPs represents a novel cAMP-downstream target for the immunomodulatory effects of VIP.

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease is Mediated Through the IL-23-->IL-17 Axis

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2007  |  Pubmed ID: 17548652

Although Crohn's disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE(2), a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE(2) exacerbate the inflammatory process in inflammatory bowel disease through the IL-23-->IL-17 axis. We assessed the effects of PGE(2) on IL-12, IL-27, and IL-23 and found that PGE(2) promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE(2) are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4(+)IL-17(+) T cells in the colonic tissue. These studies suggest that high levels of PGE(2) exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

Prostaglandin E2 Exacerbates Collagen-induced Arthritis in Mice Through the Inflammatory Interleukin-23/interleukin-17 Axis

Arthritis and Rheumatism. Aug, 2007  |  Pubmed ID: 17665454

Recently, Th17 cells, a new subset of CD4+ T cells, emerged as major players in inflammation/autoimmunity. Maintenance of the Th17 phenotype requires interleukin-23 (IL-23), whereas the Th1-promoting cytokine IL-12p70 exerts a negative effect on Th17 cell differentiation. The lipid mediator prostaglandin E(2) (PGE(2)) acts primarily as a proinflammatory agent in autoimmune conditions, through mechanisms that remain to be elucidated. The aim of this study was to investigate whether PGE(2) released in inflammatory foci activates resident dendritic cells (DCs) to express IL-23 (at the expense of IL-12) and IL-6, resulting in a shift toward Th17 cell responses.

Neuropeptides: Active Participants in Regulation of Immune Responses in the CNS and Periphery

Brain, Behavior, and Immunity. Jan, 2008  |  Pubmed ID: 17706916

PGE2-induced Metalloproteinase-9 is Essential for Dendritic Cell Migration

Blood. Jan, 2008  |  Pubmed ID: 17925490

Following antigen acquisition and maturation, dendritic cells (DCs) disengage from the extracellular matrix, cross basement membranes, and travel to draining lymph nodes to activate T cells. CCR7 expression is necessary but not sufficient for the directional migration of DCs. Prostaglandin E2 (PGE2), present in inflammatory sites, induces DC migration, presumably by enacting a migration-permissive gene expression program. Since regulation of DC migration is highly important for their use in vaccination and therapy, we examined the PGE2-induced changes in the expression of metalloproteinases (MMPs). Our results indicate that PGE2 significantly up-regulates MMP-9 expression, induces both secreted and membrane-bound MMP-9, and that in turn, DC-derived MMP-9 is essential for DC chemotaxis in response to the CCR7 ligand CCL19, Matrigel migration, and in vivo migration in both wild-type and MMP-9-deficient hosts. We conclude that DCs matured within inflammatory sites require both CCR7 and PGE2-induced MMP-9 for their directional migration to draining lymph nodes.

In Vitro Differentiation of Dendritic Cells in the Presence of Prostaglandin E2 Alters the IL-12/IL-23 Balance and Promotes Differentiation of Th17 Cells

Journal of Immunology (Baltimore, Md. : 1950). Jul, 2008  |  Pubmed ID: 18566439

PGE2, an endogenous lipid mediator released in inflammatory conditions, affects both dendritic cell (DC) differentiation and maturation. Whereas the effect of PGE2 on fully differentiated DC was studied extensively, little is known about its effects on DC differentiation. In this study, we show that bone marrow-derived DC generated in the presence of PGE2 (DCp) acquire a proinflammatory profile; produce higher levels of proinflammatory cytokines/chemokines; express higher levels of MHC class II, costimulatory molecules, and TLRs; and exhibit increased activation of the NF-kappaB-signaling pathway. In addition, DCp exhibit a different IL-12/IL-23 profile than DC generated in the absence of PGE2. The low IL-12 and high IL-23 production in LPS-stimulated DCp is associated with the down-regulation of p35 and the up-regulation of p19 expression, respectively. In agreement with the DCp proinflammatory phenotype and especially with the altered IL-12/IL-23 balance which strongly favors IL-23, DCp also affect T cell differentiation. In contrast to DC which favor Th1 differentiation, DCp promote Th17 and inhibit Th1/Th2 differentiation, in vitro and in vivo. Previous in vivo studies indicated that PGE2 had a proinflammatory effect, especially in models of autoimmune diseases. Our results suggest that the proinflammatory effects of PGE2 could be mediated, at least partially, through effects on differentiating DC and subsequent alterations in CD4+ T cell differentiation, resulting in the preferential development of pathogenic autoimmune Th17 cells.

Anti-inflammatory Neuropeptides: a New Class of Endogenous Immunoregulatory Agents

Brain, Behavior, and Immunity. Nov, 2008  |  Pubmed ID: 18598752

Resolution of inflammation and induction of immune tolerance are essential to stabilize immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure the re-establishment of immune homeostasis and maintenance of tolerance. The identification of endogenous factors that regulate these processes is crucial for the development of new therapies for inflammatory/autoimmune conditions. Neuropeptides produced during an ongoing inflammatory response emerged as endogenous anti-inflammatory agents that participate in processes leading to the resolution of inflammation and maintenance of tolerance. Anti-inflammatory neuropeptides and hormones such as vasoactive intestinal peptide, urocortin, adrenomedullin, melanocyte stimulating hormone, ghrelin, and cortistatin have beneficial effects in a variety of experimental inflammatory and autoimmune models. Their therapeutic effect has been attributed to their capacity to downregulate innate immunity, to inhibit antigen-specific T(H)1-driven responses, and to generate regulatory T cells. Finally, some of these neuropeptides have been identified as mediators of innate defense acting as natural antimicrobial peptides. Here we present the research findings in the neuropeptide immunoregulatory field, and examine possible therapies based on anti-inflammatory neuropeptides and hormones as a new pharmacologic platform.

Bone Marrow-derived Dendritic Cells Generated in the Presence of Resolvin E1 Induce Apoptosis of Activated CD4+ T Cells

Journal of Immunology (Baltimore, Md. : 1950). Oct, 2008  |  Pubmed ID: 18802056

In contrast to the role of dendritic cells (DC) in immunity and tolerance, little is known about their possible role in the resolution of inflammatory processes. In addition to the reduction in the number of infiltrating immune cells, the elimination of effector T cells already present at the inflammatory site represents an essential step toward resolution. Recently, lipid mediators such as the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their metabolites, including resolvin E1 (RvE1), have been shown to accumulate in inflammatory foci during the resolution phase. RvE1 has been reported to reduce immune cell infiltration and proinflammatory cytokine production. In this study we report that DC exposed to RvE1, especially during differentiation, acquire the capacity to induce apoptosis of activated T cells through the induction and activity of indoleamine 2,3-dioxygenase. To our knowledge, this study is the first to report on an omega-3 fatty acid derivative inducing indoleamine 2,3-dioxygenase expression in DC. RvE1-exposed DC maintain an immature chemokine receptor expression pattern even following TLR stimulation, with high CCR5 and no CCR7 expression. This effect implies that DC exposed to RvE1 and pathogens remain at the inflammatory site, instead of migrating to lymph nodes, and induce apoptosis in effector T cells infiltrating the inflammatory site. To our knowledge, the DC described in this study represent a new functional DC subtype, whose essential function resides in the resolution of inflammation.

Cannabinoid CB2 Receptor Activation Attenuates Motor and Autonomic Function Deficits in a Mouse Model of Spinal Cord Injury

Clinical Neurosurgery. 2008  |  Pubmed ID: 19248685

Modulation of Cannabinoid Receptor Activation As a Neuroprotective Strategy for EAE and Stroke

Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology. Jun, 2009  |  Pubmed ID: 19255856

Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In addition, administration of the CB(1) antagonist SR141716A reduces infarct size following ischemia/reperfusion injury. Administration of both a selective CB(2) agonist and a CB(1) antagonist has the unique property of increasing blood flow to the brain during the occlusion period, suggesting an effect on collateral blood flow. In summary, selective CB(2) receptor agonists and CB(1) receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.

CB2 Receptor Activation Attenuates Microcirculatory Dysfunction During Cerebral Ischemic/reperfusion Injury

Microvascular Research. Jun, 2009  |  Pubmed ID: 19332079

Previous studies from our laboratory indicated that selective cannabinoid CB(2) agonists were able to attenuate cerebral ischemia/reperfusion (I/R) injury. The goal of current study is to further test whether this attenuation involves cerebral microcirculatory function during I/R injury. Middle cerebral artery occlusion with reperfusion (MCAO/R) was performed in male mice. A selective CB(2) agonist was administered at different dosages and different times. Cerebral infarction volume, neurological function and cerebral microcirculatory function (leukocyte/endothelial interactions, cell adhesion molecule expression and blood-brain barrier disruption) were examined in vivo and in vitro. CB(2) knockout mice were subjected to MCAO/R following same procedures. Administration of the CB(2) agonist at middle dosage exerted optimal effects in reducing cerebral infarction and improving neurological function compared with other dosage groups and control group. Treatment with the CB(2) agonist at the optimal dose was still effective when given 3 h after MCAO. Transient ischemia significantly increased leukocyte/endothelial interactions, adhesion molecules expression and blood-brain barrier disruption which were all attenuated by pre-treatment with a CB(2) agonist. CB(2) knockout mice showed larger cerebral infarction and worse neurological function compared to wide type. In conclusion, CB(2) activation contributed to protecting the brain through the attenuation of cerebral microcirculatory dysfunction during cerebral I/R injury.

Interferon Beta Induces Mature Dendritic Cell Apoptosis Through Caspase-11/caspase-3 Activation

Blood. Aug, 2009  |  Pubmed ID: 19531658

Although interferon beta (IFNbeta) decreases relapse rate and disease activity in multiple sclerosis (MS), the mechanisms involved have not been elucidated. The present study is the first report on the apoptotic effect of IFNbeta in mature, but not immature, myeloid dendritic cells (DCs). Both exogenous IFNbeta added to DCs matured through exposure to proinflammatory cytokines and endogenous IFNbeta secreted after lipopolysaccharide stimulation induced DC cell death. Apoptosis of mature DCs required both NF-kappaB and STAT-1 activation, and was mediated through the induction of caspase-11 expression and activation of caspase-3. In vivo, we observed increased caspase-11 expression and a significant decrease in the number of splenic DCs after lipopolysaccharide administration in wt but not in STAT-1-deficient mice. Since mature DCs are major contributors to the inflammatory response and essential partners in the induction of adaptive immunity, IFNbeta-dependent elimination of activated DCs could play an essential role in re-establishing homeostasis, and might represent a new molecular mechanism for the therapeutic effect of IFNbeta in MS.

The Combination of Selective Inhibition of the Cannabinoid CB1 Receptor and Activation of the Cannabinoid CB2 Receptor Yields Improved Attenuation of Motor and Autonomic Deficits in a Mouse Model of Spinal Cord Injury

Clinical Neurosurgery. 2009  |  Pubmed ID: 20214038

Neuropeptides: Keeping the Balance Between Pathogen Immunity and Immune Tolerance

Current Opinion in Pharmacology. Aug, 2010  |  Pubmed ID: 20399708

Various neuropeptides have emerged recently as potent immunomodulatory factors with potential for their therapeutic use in immune disorders. Here we highlight the most recent data relevant in the field and we offer our opinion on how neuropeptide therapy might impact clinical immune diseases, and the challenges in this field that must be overcome before achieving medical progress. We also review recent reports describing the antimicrobial effects showed by some neuropeptides and the therapeutic, physiological, and evolutionary consequences of this new finding. Finally, we discuss how a physiologically functional neuropeptide system contributes to general health and how neuropeptides educate our immune system to be tolerant.

Dendritic Cells Transduced with Lentiviral Vectors Expressing VIP Differentiate into VIP-secreting Tolerogenic-like DCs

Molecular Therapy : the Journal of the American Society of Gene Therapy. May, 2010  |  Pubmed ID: 20068554

Dendritic cells (DCs) initiate immune responses as well as tolerance. We showed previously that the neuropeptide vasoactive intestinal peptide (VIP) suppresses innate immune responses, modulates adaptive responses by generating regulatory T cells (Treg) through the induction of tolerogenic DCs (tDCs), and has therapeutic effects in models of autoimmune/inflammatory disorders. Systemic VIP administration is limited by its short biological half-life and by its pleiotropic effects on the cardiovascular system and gastrointestinal tract. Therefore, we used lentiviral vectors to genetically engineer VIP-expressing bone marrow-derived DC (BMDC) and characterized the transduced LentiVIP-DC in terms of phenotype and therapeutic effects in models of experimental autoimmune encephalomyelitis (EAE) and cecal ligation and puncture (CLP) sepsis. LentiVIP-DCs secrete VIP, and resemble tDCs through lack of co-stimulatory molecule upregulation, lack of proinflammatory cytokine secretion, increased interleukin (IL)-10 production, and poor stimulation of allogeneic T cells. A single inoculation of LentiVIP-DC in EAE or CLP mice had therapeutic effects, which correlated with reduced expression of proinflammatory cytokines and increased IL-10 production in spinal cord and peritoneal fluid, respectively. In contrast to systemic VIP administration that requires repeated, high-dose inoculations, local delivery of VIP by LentiVIP-DC may represent a promising therapeutic tool for the treatment of autoimmune diseases and inflammatory disorders.

Docosahexaenoic Acid Prevents Dendritic Cell Maturation and in Vitro and in Vivo Expression of the IL-12 Cytokine Family

Lipids in Health and Disease. 2010  |  Pubmed ID: 20122166

Acute and chronic inflammation play essential roles in inflammatory/autoimmune conditions. Protective anti-inflammatory effects of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were reported in animal models of colitis, sepsis, and stroke. Since dendritic cells (DC) represent the essential cellular link between innate and adaptive immunity and have a prominent role in tolerance for self-antigens, we sought to investigate the impact of DHA on DC maturation and proinflammatory cytokine production.

IFN-beta Inhibits Dendritic Cell Migration Through STAT-1-mediated Transcriptional Suppression of CCR7 and Matrix Metalloproteinase 9

Journal of Immunology (Baltimore, Md. : 1950). Apr, 2010  |  Pubmed ID: 20190134

IFN-beta is an approved therapeutic option for the treatment of multiple sclerosis. The molecular mechanisms underlying the effects of IFN-beta in multiple sclerosis are not fully understood. Migration of dendritic cells (DCs) from the inflammatory site to draining lymph nodes for Ag presentation and activation of naive T cells and to the CNS for reactivation of encephalitogenic T cells requires CCR7 and matrix metalloproteinase (MMP)-9 expression. This article reports for the first time that IFN-beta inhibits CCR7 expression and MMP-9 production in mature DCs and reduces their migratory capacity. The effect of IFN-beta is mediated through STAT-1. In vivo treatment with IFN-beta results in lower numbers of DCs migrating to the draining lymph node following exposure to FITC and in reduced expression of CCR7 and MMP-9 in splenic CD11c(+) DCs following LPS administration. IFN-beta and IFN-gamma share the same properties in terms of their effects on CCR7, MMP-9, and DC migration, but they have opposite effects on IL-12 production. In addition, IFN-beta-treated DCs have a significantly reduced capacity for activating CD4(+) T cells and generating IFN-gamma-producing Th1 cells. The suppression of mature DC migration through negative regulation of CCR7 and MMP-9 expression represents a novel mechanism for the therapeutic effect of IFN-beta.

Docosahexaenoic Acid Prevents Dendritic Cell Maturation, Inhibits Antigen-specific Th1/Th17 Differentiation and Suppresses Experimental Autoimmune Encephalomyelitis

Brain, Behavior, and Immunity. Jul, 2011  |  Pubmed ID: 20854895

Docosahexaenoic acid (DHA), the most abundant essential n-3 polyunsaturated fatty acid in the CNS, emerged recently together with eicosapentaenoic acid (EPA) and DHA/EPA metabolic derivatives as a major player in the resolution of inflammation. Protective anti-inflammatory effects of DHA were reported in clinical studies and animal models of colitis, sepsis, and stroke. Here we report for the first time a beneficial effect of dietary n-3 fatty acids in experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis. In the present study we investigated the effects of DHA on the function of bone marrow-derived dendritic cells (DC) in CD4(+) T cell stimulation and differentiation. Pretreatment of DC with DHA prevented LPS-induced DC maturation, maintaining an immature phenotype characterized by low expression of costimulatory molecules and lack of proinflammatory cytokine production (IL-12p70, IL-6, and IL-23). DHA-treated DC were poor stimulators of antigen-specific T cells in terms of proliferation and Th1/Th17 differentiation. This was associated with an increase in p27(kip1), a cell cycle arresting agent, and with decreases in Tbet, GATA-3, and RORγt, master transcription factors for Th1, Th2, and Th17. In contrast, T cells co-cultured with DC-DHA express higher levels of TGFβ and Foxp3, without exhibiting a functional Treg phenotype. Similar to the in vitro results, the beneficial effect of DHA in EAE was associated with reduced numbers of IFNγ- and IL-17-producing CD4(+) T cells in both spleen and CNS.

Modulation of Dendritic Cell Function by PGE2 and DHA: a Framework for Understanding the Role of Dendritic Cells in Neuroinflammation

Clinical Lipidology. Jun, 2011  |  Pubmed ID: 21804863

Neuroinflammation characterizes various neurological disorders. Peripheral immune cells and CNS-resident glia contribute to neuroinflammation and impact CNS degeneration, recovery and regeneration. Recently, the role of dendritic cells in neuroinflammation received special attention. The function of infiltrating immune cells and resident glia is affected by various factors, including lipid mediators. Polyunsaturated fatty acids, especially n-6 arachidonic acid and n-3 docosahexaenoic acid (DHA), the most abundant in the CNS, play an important role in neuroinflammation. The major arachidonic acid bioactive derivative in immune cells, PGE2, and DHA have been reported to have opposite effects on dendritic cells in terms of cytokine production and activation/differentiation of CD4(+) T cells. Here we review the existing information on PGE2 and DHA modulation of dendritic cell function and the potential impact of these lipid mediators of dendritic cells in CNS inflammatory disorders.

Prostaglandin E2 Induces Matrix Metalloproteinase 9 Expression in Dendritic Cells Through Two Independent Signaling Pathways Leading to Activator Protein 1 (AP-1) Activation

The Journal of Biological Chemistry. Nov, 2011  |  Pubmed ID: 21940623

Dendritic Cells (DCs) play an important role in the initiation of the immune response by migrating to regional lymph nodes and presenting antigen processed at the inflammatory site to antigen-specific naïve T cells. Prostaglandin E2 (PGE2) has been reported to play an essential role in DC migration. We reported previously that PGE2 induces matrix metalloproteinase 9 (MMP-9) expression in DCs and that PGE2-induced MMP-9 is required for DC migration in vivo and in vitro. In this study, we investigated the signaling mechanisms involved in PGE2-induced MMP-9 expression in DCs. We show that PGE2-induced MMP-9 expression is mediated primarily through the EP2/EP4 → cAMP → protein kinase A (PKA)/PI3K → ERK signaling pathway, leading to c-Fos expression, and through JNK-mediated activation of c-Jun in a PKA/PI3K/ERK-independent manner. EP2 and EP4 receptor agonists, as well as cAMP analogs, mimic the up-regulation of MMP-9 by PGE2. PKA, PI3K, and ERK inhibitors abolished PGE2- and cAMP-induced c-Fos and MMP-9 up-regulation, and ERK activation was required for the binding of activator protein 1 (AP-1) transcription factor to the MMP-9 promoter. Our results describe a new molecular mechanism for the effect of PGE2 on MMP-9 production in DCs that could lead to future therapeutic approaches using ERK inhibitors to regulate DC migration.

Modulation of Inflammatory Responses by a Cannabinoid-2-selective Agonist After Spinal Cord Injury

Journal of Neurotrauma. Dec, 2011  |  Pubmed ID: 21970496

The goal of the current investigation was to evaluate the mechanisms through which administration of a selective cannabinoid-2 (CB2) agonist (O-1966) modifies inflammatory responses and helps to improve function following spinal cord injury. A comparison of motor function, autonomic function, and inflammatory responses was made between animals treated with O-1966 (5 mg/kg IP) and animals treated with vehicle 1 h and 24 h following contusion injury to the spinal cord. Motor function was significantly improved in the treated animals at each time point during the 14 days of evaluation. The percentage of animals able to spontaneously void their bladder was also greater over the entire study period in the group treated with the selective CB2 agonist. Seven days following injury there was a significant reduction in both hematopoietic and myeloid cell invasion of the spinal cord, and a reduction in the number of immunoreactive microglia. The results of the evaluation of chemokine/cytokine expression and inflammatory cell invasion also demonstrated a significant effect of treatment on inflammatory reactions following injury. Two days after injury, animals treated with O-1966 had significant reductions in CXCL-9 and CXCL-11, and dramatic reductions in IL-23p19 expression and its receptor IL-23r. Treatment with O-1966 also caused inhibition of toll-like receptor expression (TLR1, TLR4, TLR6 and TLR7) following injury. These results demonstrate that the improvement in motor and autonomic function resulting from treatment with a selective CB2 agonist is associated with a significant effect on inflammatory responses in the spinal cord following injury.

Vasoactive Intestinal Peptide: a Neuropeptide with Pleiotropic Immune Functions

Amino Acids. Dec, 2011  |  Pubmed ID: 22139413

Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide/neurotransmitter, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors. VIP has pleiotropic effects as a neurotransmitter, immune regulator, vasodilator and secretagogue. This review is focused on VIP production and effects on immune cells, VIP receptor signaling as related to immune functions, and the involvement of VIP in inflammatory and autoimmune disorders. The review addresses present clinical use of VIP and future therapeutic directions.