Differential Activity of IL-12 and IL-23 in Mucosal and Systemic Innate Immune Pathology

Uhlig, Holm H.; McKenzie, Brent; Hüe, Sophie; Thompson, Claire; Joyce-Shaikh, Barbara; Štěpánková, Renata; Robinson, N.W.; Buonocore, Sofia; Tlaskalová‐Hogenová, Helena; Daniel, J.; Powrie, Fiona

doi:10.1016/j.immuni.2006.05.017

Cited by 601 publications

(538 citation statements)

References 42 publications

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“…2). Functional studies with genetically engineered animals and IL 23 p19 and p40 blockers suggested that blockade of these cytokine subunits might effectively suppress intestinal inflammation in mouse models of colitis [98][99][100][101][102][103][104] . In particular, IL 23 inhibition was effective and prevented activation of T cells and innate lymphoid cells and tissue destruction in vivo.…”

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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“…The current view of mouse Th17 development is that TGF␤1 and IL-6 are the key cytokines that initiate the differentiation process and that IL-23 plays an essential role in the expansion and maintenance of this lineage. Support for the notion of an IL-23/IL-17 axis has been provided by a number of models of autoimmunity (6,(8)(9)(10)(11)26,39,(44)(45)(46), but despite these compelling data in mice, a systematic analysis of human Th17 differentiation from naive cells has not yet been undertaken.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have supported the notion of a role of IL-23 in autoimmune responses, and a preponderance of evidence indicates that this cytokine may be more clinically relevant than its close relative IL-12 in causing autoimmunity (8)(9)(10)(11)45). The recent discovery of the relationship between IL-23R single-nucleotide polymorphisms and the prevalence of inflammatory bowel disease highlights the relevance of this cytokine in human autoimmune disease (48).…”

Section: Il-17 Regulation In Human T Cellsmentioning

confidence: 94%

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Chen¹,

Tato²,

Muul³

et al. 2007

Arthritis & Rheumatism

312

281

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“…It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known.…”

Section: Introductionmentioning

confidence: 99%

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

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Intestinal CD103 1 DC promote the differentiation of Foxp3 1 Treg from naïve CD4 1 T cells through mechanisms involving TGF-b and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103 1 DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103 1 DC, which is associated with lower expression of tgfb2 and aldh1a2. Accordingly, CD103 1 DC taken from colitic mice are impaired in their ability to induce Foxp3 1 Treg and instead favour the emergence of IFN-c-producing CD4 1 T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103 1 DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103 1 DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103 1 DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.Key words: Colitis . DC . Intestinal immunity . Ontogeny . Treg IntroductionThe intestinal immune system must maintain a fine balance between harmless responses to food and commensal bacteria and protective immunity to invading pathogens. It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known. One possibility is that these activities are mediated by distinct DC populations and indeed many subtypes of DC have been identified in the gut [4]. It has been proposed that resident gutconditioned DC may favour tolerogenic responses, whereas newly recruited inflammatory DC may drive host protective immunity.Alternatively, tissue-resident DC may adopt distinct functions under homeostatic and inflammatory conditions [4,5].We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10]. Under homeostatic conditions, CD103 1 DC in MLN promote the development of Foxp3 1 Treg. By contrast, the reciprocal CD103 À MLN DC population displays a more pro-inflammatory phenotype and appears to represent a developmentally distinct DC population [9].In intestinal inflammation, immune regulatory pathways that normally promote tolerance in the intestine break down. Whether this is attributable to changes in DC populations or their function in the MLN is not known. Here, we show that in colitic mice, the tolerogenic properties of CD103 1 MLN DC are lost and that this APC population now drives inflammatory T-cell responses that may c...

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Differential Activity of IL-12 and IL-23 in Mucosal and Systemic Innate Immune Pathology

Cited by 601 publications

References 42 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

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Differential Activity of IL-12 and IL-23 in Mucosal and Systemic Innate Immune Pathology

Cited by 601 publications

References 42 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

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Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells