Oxazolone Colitis, a Th2 Colitis Model Resembling Ulcerative Colitis, Is Mediated by IL-13-Producing NK-T Cells

Heller, Frank; Fuss, Ivan J.; Nieuwenhuis, Edward E. S.; Blumberg, Richard S.; Strober, Warren

doi:10.1016/s1074-7613(02)00453-3

Cited by 602 publications

(537 citation statements)

References 46 publications

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“…Consistently, IL 17A inactivation did not result in amelioration of experimental colitis in mice 84,85 . In addition to IFNγ and IL 17A blockers, two prospective studies did not show efficacy of anti IL 13 antibodies (anrukinzumab, tralokinumab) in patients with ulcerative colitis despite promising results in animal models of colitis [86][87][88][89] . In contrast to these observations, additional cytokine blockers have shown more promis ing results in clinical trials that will be reviewed in the next paragraphs (FIGS 3,4).…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

403

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“…Indeed, out of almost 40 murine models of IBD, only a handful have been associated with a Th2 pattern of cytokine expression [14][15][16][17][18][19][20][21] . In these models, IL-4 is upregulated, frequently with elevations of IL-13 and/or IL-5.…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte-Dependent and Th2 Cytokine-Associated Colitis in Mice Deficient in Wiskott-Aldrich Syndrome Protein

et al. 2007

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Background & Aims: Controversy exists as to whether patients with inflammatory bowel disease have an underlying immunodeficiency. We have focused on a murine model of the Wiskott-Aldrich syndrome, an immunodeficiency in which autoimmunity can manifest in the form of an inflammatory bowel disease-like illness. Wiskott-Aldrich syndrome protein (WASP) deficiency in mice results in similar clinical features. We characterized the colitis in WASP-deficient mice.

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“…Inflammatory bowel disorders induce intestinal pathology that is associated with elevated proinflammatory cytokines (1,2). Levels of TNF-␣ and IFN-␥ are high in Crohn's disease (1), whereas IL-13, a Th2-type cytokine, drives the pathophysiology of oxazalone colitis, an experimental model with pathological features similar to ulcerative colitis (1,3). Further evidence points to IL-13 as the factor responsible for the pathogenesis of asthma (4 -7).…”

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confidence: 99%

“…For example, administration of IL-13 to the airways of mice results in distinctive asthmatic pathology of inflammatory cell infiltration, airway hyperresponsiveness, and mucus hypersecretion (4,5), while mice genetically deficient for IL-13 fail to develop this pathology when challenged with model airway allergens (6). IL-13-secreting NKT cells have been implicated in the pathogenesis of both experimental asthma and ulcerative colitis models (3,8), and NK cells have been implicated in the development of allergen-induced airway inflammation in mice (9), although it is not known whether they contribute to the responses following Th2-inducing infection. Many pathological features associated with both asthma and inflammatory bowel disorders are identical with those induced by intestinal nematode infection of both the small and large bowel (3,7,10).…”

mentioning

confidence: 99%

“…IL-13-secreting NKT cells have been implicated in the pathogenesis of both experimental asthma and ulcerative colitis models (3,8), and NK cells have been implicated in the development of allergen-induced airway inflammation in mice (9), although it is not known whether they contribute to the responses following Th2-inducing infection. Many pathological features associated with both asthma and inflammatory bowel disorders are identical with those induced by intestinal nematode infection of both the small and large bowel (3,7,10). These parasites induce in the host a strong Th2 response (10), but the etiology, in particular the role of cytokines, in intestinal tissue remodeling during these infections is poorly defined.…”

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confidence: 99%

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Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

McDermott

Humphreys

Forman

et al. 2005

The Journal of Immunology

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IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays a major role in the control of gut nematode infection and associated immunopathology. The current paradigm is that these effects are due to T cell-derived IL-13. We show in this study that an innate source of IL-13, the intraepithelial NK cell, is responsible for the disruption of intestinal tissue architecture and induction of goblet cell hyperplasia that characterizes infection with the intestinal helminth Trichinella spiralis. IL-13 or IL-4Rα (but not IL-4) null mice failed to induce intestinal pathology. Unexpectedly, SCID and athymic mice developed the same pathology found in immunocompetent mice following infection. Moreover, immunodeficient mice expressed IL-13 in the intestine, and abnormal mucosal pathology was reduced by in vivo administration of a soluble IL-13 antagonist. IL-13 expression was induced in non-T intraepithelial CD3− NK cells. Epithelial cells expressed the IL-13 signaling receptor, IL-13Rα1, and after infection, IL-4Rα. Furthermore, the soluble IL-13 decoy receptor IL-13Rα2, which regulates IL-13 responses, was also induced upon infection. These data provide the first evidence that intestinal tissue restructuring during helminth infection is an innate event dependent on IL-13 production by NK cells resident in the epithelium of the intestine.

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Oxazolone Colitis, a Th2 Colitis Model Resembling Ulcerative Colitis, Is Mediated by IL-13-Producing NK-T Cells

Cited by 602 publications

References 46 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Lymphocyte-Dependent and Th2 Cytokine-Associated Colitis in Mice Deficient in Wiskott-Aldrich Syndrome Protein

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

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