A pathogenic role for T cell–derived IL-22BP in inflammatory bowel disease

Pelczar, Penelope; Witkowski, Mario; Pérez, Laura García; Kempski, Jan; Hammel, Anna; Brockmann, Leonie; Kleinschmidt, Dörte; Wende, Sandra; Haueis, Cathleen; Bedke, Tanja; Witkowski, Marco; Krasemann, Susanne; Steurer, Stefan; Booth, Carmen J.; Busch, Philipp; König, Alexandra; Rauch, Ursula; Benten, Daniel; Izbicki, Jakob R.; Rösch, Thomas; Lohse, Ansgar W.; Strowig, Till; Gagliani, Nicola; Flavell, Richard A.; Huber, Samuel

doi:10.1126/science.aah5903

Cited by 124 publications

(172 citation statements)

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“…The results of the phase III study in patients with ulcerative colitis are expected in 2017. Moreover, IL 22 therapy or modulation of IL 22 binding protein have been tested successfully in mouse colitis models and proposed as new approaches for IBD therapy 130 . The IL 22 cytokine directly activates proliferation of intes tinal epithelial cells via STAT3 activation and induces production of protective barrier proteins such as REG proteins 131 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

488

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

488

403

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“…IL-22-binding protein (IL-22BP), as a soluble binding receptor and antagonist of IL-22, can compete with membrane-bound IL-22 receptor 1 for the binding of free cytokine molecules and thus prevent IL-22 from generating a signal (Dumoutier et al, 2001). CD4 + T cell-derived IL-22BP demonstrated a pathogenic role in inflammatory bowel disease (IBD) (Pelczar et al, 2016). Orally fed Bacillus mixture was shown to upregulate IL-22 mRNA expression in the small intestine in response to E. coli challenge (Yang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Oral Administration of Lactobacillus rhamnosus GG Ameliorates Salmonella Infantis-Induced Inflammation in a Pig Model via Activation of the IL-22BP/IL-22/STAT3 Pathway

Yang

et al. 2017

Front. Cell. Infect. Microbiol.

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The high rate of Salmonella enterica serovar Infantis (S. Infantis) infection poses significant risk for the development of non-typhoidal Salmonella gastroenteritis. However, efficient strategies to prevent or treat the infection remain elusive. Here, we explored the effect of the probiotic Lactobacillus rhamnosus GG (LGG) administration in preventing S. Infantis infection in a pig model. Probiotic LGG (1.0 × 1010 CFU/day) was orally administered to newly weaned piglets for 1 week before S. Infantis challenge. LGG pretreatment reduced the severity of diarrhea and alleviated intestinal inflammation caused by S. Infantis. Pre-administration of LGG excluded Salmonella from colonization of the jejunal mucosa but increased the abundance of Bifidobacterium in the feces. LGG promoted the expansion of CD4+ T-bet+ IFNγ+ T cells but attenuated S. Infantis-induced increases in the percentage of CD4+ IFNγ+ T cells and serum interleukin (IL)-22 levels in peripheral blood after S. Infantis challenge. In the small intestine, LGG pretreatment upregulated expression of the transcription factor T-bet but downregulated the S. Infantis-induced increase of CD4+ IFNγ+ T cells in Peyer's patches and IL-7Rα expression in the jejunum. Notably, LGG-treated pigs had enhanced expression of IL-22 and activated STAT3 in the ileum in response to S. Infantis infection. Pretreatment of pigs with LGG also elevated intestinal IL-22-binding protein production in response to S. Infantis challenge. In contrast, LGG consumption reduced the S. Infantis-induced increase in the number of CCL20-expressing cells in the jejunum. Our results suggest that the mechanism by which LGG ameliorates the intestinal inflammation caused by S. Infantis involves the upregulation of T-bet, activation of STAT3, and downregulation of CCL20.

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“…TRM amongst patients that developed acute GI GVHD IL-22 levels above the median was 46.9% compared to patients with IL-22 levels below the median of 20% at 1 year, p=0.6, Figure 1B. IL-22 binding protein (IL-22BP) is a soluble, potent inhibitor of IL-22 and is thought to regulate its downstream effects and has been found to be enhanced during active colitis of patients with IBD. (11,12) We hypothesized that IL-22BP levels would be elevated in patients with GI GVHD and that these levels would be inversely correlated with IL-22 levels. IL-22BP levels at day 30 post-transplant had a negative correlation with IL-22 levels at day 30 post-transplant (r=-0.2, p=0.03) but had no association with the development of GI GVHD.…”

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confidence: 99%