Erratum: Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

Atreya, Raja; Mudter, Jonas; Finotto, Susetta; Mullberg, Jürgen; Jostock, Thomas; Wirtz, Stefan; Schutz, M.M.; Bartsch, Brigitte; Holtmann, Martin; Becker, Christoph; Strand, Dennis; Czaja, J; Schlaak, Joerg F.; Lehr, Hans‐Anton; Autschbach, Frank; Schürmann, G.; Nishimoto, N.; Yoshizaki, Kazuyuki; Ito, Hiromu; Kishimoto, T; Galle, Peter R.; Rose–John, Stefan

doi:10.1038/nm1110-1341

Cited by 82 publications

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“…IL 6 is a proinflammatory cytokine activating immune cells 90,91 . In patients with IBD, levels of IL 6 and its agonistic soluble receptor (sIL 6R) are induced and mediate activation of T cells and their resistance against programmed cell death (apoptosis) 92 . In experi mental colitis models, IL 6R blockade was effective in suppressing intestinal inflammation.…”

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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“…Here, we show that inflammation dampens the tolerogenic properties of MLN CD103 1 DC and induces an inflammatory phenotype amongst these cells. CD103 1 DC isolated from the MLN of colitic mice promoted Th1 responses and produced high levels of IL-6, both of which mediate colitogenic activity [14,15].Our results suggest that the altered function of CD103 1 DC from inflamed MLN was not attributable to changes in the subset composition of this population. Firstly, as observed under steady-state conditions, there was no precursor-product rela- …”

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confidence: 66%

“…2D). As the pro-inflammatory cytokines IFN-g and IL-6 contribute to the pathogenesis of both inflammatory bowel disease and experimental models of colitis [14][15][16], we analysed their production in the culture supernatants. We found that CD103 1 DC taken from colitic mice induced increased secretion of IFN-g in the culture medium when compared with CD103 1 DC from steady-state mice.…”

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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“…1a-e). Mechanistically, increased expression of matrix metalloprotease-9 (MMP9, as a marker of vascular remodelling) 23 , F4/80 (as a marker of macrophages) 24,25 and IL-6 (as a marker of inflammation) 16,[26][27][28][29][30] were seen in the aorta (Fig. 1f).…”

Section: Resultsmentioning

confidence: 99%

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

et al. 2015

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Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. Underlying mechanisms of the condition remain unclear. Here we show that granulocyte macrophage colony-stimulating factor (GM-CSF) is a triggering molecule for this condition. Transcription factor Krüppel-like factor 6 (KLF6)-myeloid-specific conditional deficient mice exhibit this aortic phenotype when subjected to aortic inflammation. Mechanistically, KLF6 downregulates expression and secretion of GM-CSF. Administration of neutralizing antibody against GM-CSF prevents the condition in these mice. Conversely, administration of GM-CSF in combination with aortic inflammation to wild-type mice is sufficient to induce the phenotype, suggesting the general nature of effects. Moreover, patients with this condition show highly increased circulating levels of GM-CSF, which is also locally expressed in the dissected aorta. GM-CSF is therefore a key regulatory molecule causative of this aortopathy, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

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Erratum: Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

Abstract: In the version of this article initially published, the fourth image in Figure 4b was a duplication of the third image. The error has been corrected in the HTML and PDF versions of the article.nature medicine volume 16 | number 11 | november 2010 1341 e r r ata

Cited by 82 publications

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Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

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

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

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Erratum: Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

Abstract: In the version of this article initially published, the fourth image in Figure 4b was a duplication of the third image. The error has been corrected in the HTML and PDF versions of the article.nature medicine volume 16 | number 11 | november 2010 1341 e r r ata

Cited by 82 publications

References 0 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

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

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

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