Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation

Maxwell, Joseph R.; Zhang, Yu; Brown, W. A.; Smith, Carole L.; Byrne, Fergus R.; Fiorino, Mike; Stevens, Erin; Bigler, Jeannette; Davis, John A.; Rottman, James B.; Budelsky, Alison; Symons, Antony; Towne, Jennifer E.

doi:10.1016/j.immuni.2015.08.019

Cited by 288 publications

(258 citation statements)

References 41 publications

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“…For instance, the anti IFNγ anti body fontolizumab showed low efficacy in patients for treatment of active Crohn's disease 80 . Moreover, the anti IL 17A antibody secukinumab resulted in aggrav ation of Crohn's disease in many patients, possibly owing to the protective effects of IL 17A on gut epi thelial cells [81][82][83] . Consistently, IL 17A inactivation did not result in amelioration of experimental colitis in mice 84,85 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

530

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

530

403

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“…Third, Th17 cells seem to have a yin-yang role in human health. Mice devoid of IL-17 signaling manifest alterations in their microbiotas and suffer from increased intestinal permeability and bacterial translocation to systemic sites after infectious insults of the gut (15,16,53). Additionally, loss of Th17 populations during infections by either simian virus or HIV has been associated with intestinal dysbiosis, systemic microbial translocation, and disease progression (53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

“…They secrete the cytokines IL-17A, IL-17F, and IL-22, which induce the production of antimicrobial peptides and tight junction proteins from intestinal epithelial cells, thereby buttressing gut barrier integrity (15)(16)(17). Moreover, IL-17A and IL-17F promote the recruitment of neutrophils via the release of granulocyte colony-stimulating factor, thereby helping to defend the host against infections by fungi and extracellular bacteria (18).…”

mentioning

confidence: 99%

Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice

Tan

Sefik

Geva‐Zatorsky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

363

287

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Th17 cells accrue in the intestine in response to particular microbes. In rodents, segmented filamentous bacteria (SFB) induce intestinal Th17 cells, but analogously functioning microbes in humans remain undefined. Here, we identified human symbiont bacterial species, in particular Bifidobacterium adolescentis, that could, alone, induce Th17 cells in the murine intestine. Similar to SFB, B. adolescentis was closely associated with the gut epithelium and engendered cognate Th17 cells without attendant inflammation. However, B. adolescentis elicited a transcriptional program clearly distinct from that of SFB, suggesting an alternative mechanism of promoting Th17 cell accumulation. Inoculation of mice with B. adolescentis exacerbated autoimmune arthritis in the K/BxN mouse model. Several off-the-shelf probiotic preparations that include Bifidobacterium strains also drove intestinal Th17 cell accumulation.

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“…41 However, targeted therapies against IL-17A in Crohn's disease have been proven ineffective 55,56 and recent studies have shown that IL-17A is important for maintaining intestinal barrier integrity and has a protective role in regard to the development of colitis. 57,58 Further, it is becoming more apparent that the T H 17-cell lineage has a degree of heterogeneity with regards to pathogenicity. For example, T H 17 cells differentiated in the presence of TGFb are less pathogenic and produce higher levels of IL-10, whereas cells differentiated in the presence of IL-23 are more pathogenic and can produce IFN-g. 59,60 In addition, T H 17 cells have a degree of plasticity and fate-mapping studies have shown that ''ex-T H 17'' cells lose their ability to produce IL-17A altogether and exclusively produce IFN-g under certain conditions.…”

Section: Hic1 Is Required To Limit Stat3 Signaling In T H 17 Cellsmentioning

confidence: 99%