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In JoVE (1)
Other Publications (15)
- Gastroenterology
- Gastroenterology
- Gastroenterology
- Journal of Cellular and Molecular Medicine
- Gut
- American Journal of Physiology. Gastrointestinal and Liver Physiology
- Gastroenterology
- Gastroenterology
- European Journal of Immunology
- Gastroenterology
- Gastroenterology
- American Journal of Physiology. Gastrointestinal and Liver Physiology
- Inflammatory Bowel Diseases
- Journal of Immunology (Baltimore, Md. : 1950)
- The American Journal of Pathology
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Articles by Waliul I. Khan in JoVE
JoVE General
Onderzoeken darmontsteking in DSS-geïnduceerde Model van IBD
Experimentele modellen van inflammatoire darmziekte hebben ons de complexe aangeboren en adaptieve immuunrespons geassocieerd met pathogenese te onderzoeken. Met behulp van histologische scoring, kwantificering van pro-inflammatoire cytokines en myeloperoxidase activiteit, kan men beginnen met deze reacties gezien bij inflammatoire darmziekten te beoordelen.
Other articles by Waliul I. Khan on PubMed
Visceral Hyperalgesia and Intestinal Dysmotility in a Mouse Model of Postinfective Gut Dysfunction
We established the concept that transient enteric infection may lead to persistent gut dysfunction, evident in vitro, in nematode-infected mice. The present study determined whether gut dysfunction in this model involves motor and sensory changes reminiscent of changes found in patients with postinfective irritable bowel syndrome (PI-IBS) and investigated underlying mechanisms.
CD4+ T-cell Modulation of Visceral Nociception in Mice
Although inflammatory and immune cells are present in the gut in the absence of pathology, their presence does not result in sensitization of sensory nerves, implying the existence of a local antinociceptive influence. We hypothesized that a component of the immune system exerts an antinociceptive influence, thus enabling the gut to function in the absence of undue pain or discomfort.
Antidepressants Attenuate Increased Susceptibility to Colitis in a Murine Model of Depression
Psychiatric factors may determine gastrointestinal health outcomes. Here, we used a model of depression based on neonatal maternal separation (MS) to identify alterations in gut physiology and to assess its association with increased sensitivity to experimental colitis in adulthood. We also examined whether antidepressant therapy attenuates the increased susceptibility to colitis.
IL-9 Enhances Growth of ICC, Maintains Network Structure and Strengthens Rhythmicity of Contraction in Culture
Interstitial cells of Cajal (ICC) play a critical role in the control of gastrointestinal motility as pacemaker cells and as regulators of enteric innervation. ICC are one of the first cell types that are injured during an inflammatory process and maintenance of ICC health or promotion of growth and development maybe crucial in recovery after injury. The aim of this study was to evaluate the role of IL-9 in the growth, development and maintenance of ICC in culture. IL-9 in concentrations from 0.02 to 1 microg/ml promoted individual ICC growth and maintenance of the ICC network structure inside tissue explants under culture conditions. The number of ICC grown out of the explants increased significantly at day 4 of culture in the presence of 0.02, 0.5 and 1 microg/ml IL-9. In the presence of 0.5 microg/ml IL-9, explants in culture maintained a higher frequency and stabilized the frequency of spontaneous contractile activity. The ultrastructure of the ICC after 4 days in culture was similar to that in situ. Our data indicate that IL-9 promotes ICC growth in culture and it can be hypothesized that IL-9 is a critical factor in the maintenance of ICC health and ICC repair after injury.
CD4+ T Cell-mediated Immunological Control of Enterochromaffin Cell Hyperplasia and 5-hydroxytryptamine Production in Enteric Infection
Enterochromaffin (EC) cells are dispersed throughout the gastrointestinal (GI) mucosa and are the main source of 5-hydroxytryptamine (5-HT) in the gut. 5-HT has been implicated in the pathophysiology of several GI disorders, but the mechanisms regulating 5-HT production in the gut are unknown.
Cytokine Modulation of Muscarinic Receptors in the Murine Intestine
The extent to which gut motility and smooth muscle contractility are altered by intestinal inflammation depends on the nature of the underlying immune activation. The muscarinic receptor on smooth muscle plays a critical role in mediating acetylcholine-driven motor function. We examined the ability of cytokines to influence muscarinic receptor characteristics on intestinal longitudinal muscle and related the findings to studies on carbachol-induced contraction. Cells were isolated from longitudinal muscle myenteric plexus (LMMP). Cytokine receptor expression, muscle contractility, and muscarinic agonist receptor characteristics were examined by agonist displacement of [N-methyl-(3)H]scopolamine ([(3)H]NMS) binding. The TGF-beta1 receptor (543 bp) and the IFN-gamma receptor 1 (660 bp) were identified on smooth muscle cells. Scatchard analysis revealed dissociation constant and maximum binding values for [(3)H]NMS of 2.6 nM and 2.4 x 10(4) sites/cell, respectively, in control cells. Nematode infection was accompanied by a reduction in inhibitory constant of the high-affinity sites (K(H)), and this was independent of signal transduction and activator of transcription 6. Preincubation with TGF-beta1 enhanced longitudinal muscle contractility and decreased the K(H) to 2.2 pM (increased muscarinic receptor affinity), whereas preincubation with IFN-gamma increased the K(H) to 0.4 muM (decreased muscarinic receptor affinity) and decreased longitudinal muscle contractility. Preincubation of LMMP with IL-13 decreased the K(H) to 0.2 nM. Cytokines exert differential effects on the muscarinic receptor on intestinal longitudinal smooth muscle. These findings explain the basis for altered muscle contractility observed in Th1 and Th2 models of inflammation, as well as in the post-nematode-infected state.
Serotonin Has a Key Role in Pathogenesis of Experimental Colitis
Mucosal changes in inflammatory bowel disease are characterized by ulcerative lesions accompanied by a prominent infiltrate of immune cells as well as alteration in serotonin (5-hydroxytryptamine [5-HT])-producing enterochromaffin cells. We investigated the role of 5-HT in colonic inflammation in mice.
Reactivation of Inflammatory Bowel Disease in a Mouse Model of Depression
Patients with inflammatory bowel disease (IBD) frequently also have depression, yet little is known of its role in IBD pathogenesis. We investigated whether the development of depression after the establishment of chronic inflammation reactivates an acute relapse of IBD and underlying pharmacologic mechanisms in mouse models.
CD4+ T-cell-mediated Anti-tumor Immunity Can Be Uncoupled from Autoimmunity Via the STAT4/STAT6 Signaling Axis
Previous reports have suggested that autoimmune sequelae may be an unavoidable consequence of successful immunization against tumor-associated antigens, which are typically non-mutated self-antigens. Using a melanoma model, we demonstrated that CD4(+) T-cell-mediated anti-tumor immunity and autoimmunity could be separated by modulating the STAT4/STAT6 signaling axis. Our results have revealed an unexpected dichotomy in the effector phase following cancer vaccination where anti-tumor immunity is mediated via a STAT6 and IL-4-dependent pathway, whereas autoimmune pathology is mediated via STAT4 through a mechanism that relies partially on IFN-gamma. Our results offer a possibility to elicit specific anti-tumor responses without triggering unwanted tissue autoimmune diseases.
Mucin Gene Deficiency in Mice Impairs Host Resistance to an Enteric Parasitic Infection
Hyperplasia of mucin-secreting intestinal goblet cells accompanies a number of enteric infections, including infections by nematode parasites. Nevertheless, the precise role of mucins in host defense in nematode infection is not known. We investigated the role of the mucin (Muc2) in worm expulsion and host immunity in a model of nematode infection.
Chronic Gastrointestinal Inflammation Induces Anxiety-like Behavior and Alters Central Nervous System Biochemistry in Mice
Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms.
Mechanisms Underlying Gut Dysfunction in a Murine Model of Chronic Parasitic Infection
Irritable bowel syndrome (IBS) is common in countries where chronic parasitic infestations are endemic. However, the relationship between parasitic infection and IBS is not clear. The aim of this study was to examine whether chronic parasitic infection is accompanied by gut dysfunction and whether the continued presence of the parasite is required for the maintenance of the dysfunction. We used chronic Trichuris muris infection in Th1-biased susceptible AKR mice to evaluate this relationship. AKR mice were infected with T. muris and were euthanized on various days postinfection (pi) to examine worm burden, muscle function, and immune and inflammatory responses. Mice were treated with the anthelmintic oxantel pamoate to assess the effect of eradication of infection on muscle function. Infection resulted in persistence of the parasite, elevated IFN-γ, and increased MPO activity evident at 45 days pi. This was accompanied by a reduction in muscle contractility and excitatory innervation. Whereas parasite eradication at 7 days pi normalized IFN-γ and muscle contractility, eradication at 28 days pi failed to normalize muscle contractility. Administration of dexamethasone after parasite eradication normalized all parameters. Anthelmintic treatment improved histology except for eosinophils, which were normalized by subsequent dexamethasone therapy. Persistent gut dysfunction is independent of the continued presence of the parasite and is maintained by inflammatory process that includes eosinophils. Thus data in this preclinical model suggest that parasitic infection could be a cause of IBS, and the lack of symptomatic improvement following eradication is insufficient evidence to refute a causal relationship between the infection and IBS.
Adoptive Transfer of Macrophage from Mice with Depression-like Behavior Enhances Susceptibility to Colitis
Depression is common in patients with inflammatory bowel disease (IBD) but the pathway is not well understood. We examined whether the locus of susceptibility to colitis in mice with depression-like behavior (DLB) resides with the macrophage and implicates the vagus nerve.
A Mouse Model of Airway Disease: Oncostatin M-induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis is STAT6 Independent
Oncostatin M (OSM), a pleiotropic cytokine of the gp130 cytokine family, has been implicated in chronic allergic inflammatory and fibrotic disease states associated with tissue eosinophilia. Mouse (m)OSM induces airway eosinophilic inflammation and interstitial pulmonary fibrosis in vivo and regulates STAT6 activation in vitro. To determine the requirement of STAT6 in OSM-induced effects in vivo, we examined wild-type (WT) and STAT6-knockout (STAT6(-/-)) C57BL/6 mouse lung responses to transient ectopic overexpression of mOSM using an adenoviral vector (AdmOSM). Intratracheal AdmOSM elicited persistent eosinophilic lung inflammation that was abolished in STAT6(-/-) mice. AdmOSM also induced pronounced pulmonary remodeling characterized by goblet cell hyperplasia and parenchymal interstitial fibrosis. Goblet cell hyperplasia was STAT6 dependent; however, parenchymal interstitial fibrosis was not. OSM also induced airway hyperresponsiveness in WT mice that was abolished in STAT6(-/-) mice. OSM stimulated an inflammatory signature in the lungs of WT mice that demonstrated STAT6-dependent regulation of Th2 cytokines (IL-4, IL-13), chemokines (eotaxin-1/2, MCP-1, keratinocyte chemoattractant), and extracellular matrix modulators (tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-13), but STAT6-independent regulation of IL-4Rα, total lung collagen, collagen-1A1, -1A2 mRNA, and parenchymal collagen and α smooth muscle actin accumulation. Thus, overexpression of mOSM induces STAT6-dependent pulmonary eosinophilia, mucous/goblet cell hyperplasia, and airway hyperresponsiveness but STAT6-independent mechanisms of lung tissue extracellular matrix accumulation. These results also suggest that eosinophil or neutrophil accumulation in mouse lungs is not required for OSM-induced lung parenchymal collagen deposition and that OSM may have unique roles in the pathogenesis of allergic and fibrotic lung disease.
Serotonin Activates Dendritic Cell Function in the Context of Gut Inflammation
Mucosal inflammation in the gut is characterized by infiltration of innate and adaptive immune cells and by an alteration in serotonin-producing enterochromaffin cells. We investigated the role of serotonin in the function of dendritic cells (DCs) and sequential T-cell activation in relation to generation of gut inflammation. DCs isolated from tryptophan hydroxylase-1-deficient (TPH1(-/-)) mice, which have reduced serotonin in the gut, and wild-type (TPH1(+/+)) mice with or without dextran sulfate sodium (DSS)-induced colitis were stimulated with lipopolysaccharide to assess interleukin-12 (IL-12) production. Isolated DCs from TPH1(+/+) and TPH1(-/-) mice were also cocultured with CD4(+) T cells of naive TPH1(+/+) mice to assess the role of serotonin in priming T cells. In addition, serotonin-pulsed DCs were transferred to TPH1(-/-) mice to assess the effect on DSS-induced colitis. Consistent with a reduced severity of colitis, DCs from DSS-induced TPH1(-/-) mice produced less IL-12 compared with the TPH1(+/+) mice. In vitro serotonin stimulation restored the cytokine production from TPH1(-/-) DCs and adoptive transfer of serotonin-pulsed DCs into TPH1(-/-) up-regulated colitis. Furthermore, CD4(+) T cells primed by TPH1(-/-) DCs produce reduced the levels of IL-17 and interferon-γ. This study provides novel information on serotonin-mediated immune signaling and promotion of interactions between innate and adaptive immune responses in the context of gut inflammation, which may ultimately lead to improved strategies to combat gut inflammatory disorders.
