IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease

Kobayashi, Taku; Okamoto, Susumu; Hisamatsu, Tadakazu; Kamada, Nobuhiko; Chinen, Hiroshi; Saito, Ryosuke; Kitazume, Mina T.; Nakazawa, Atsushi; Sugita, Akira; Koganei, Kazutaka; Isobe, Ken‐ichi; Hibi, Toshifumi

doi:10.1136/gut.2007.135053

Cited by 491 publications

(372 citation statements)

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“…Furthermore, genetic RORγ deficiency of T cells pre vented T cell transfer of colitis in RAG knockout mice 84 . As RORA and RORC proteins, as well as T H 17 cytokines, are augmented in patients with IBD 121,122 , these data suggested that targeting of ROR proteins might be useful in these patients. Moreover, both genetic and pharmacological (via DNAzyme) blockade of GATA3, a key transcription factor for T H 2 cytokine gene tran scription, ameliorated chronic oxazolone mediated and TNBS (2,4,6 trinitrobenzenesulfonic acid) mediated colitis in mice 119 .…”

Section: T Cellmentioning

confidence: 94%

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: 94%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

403

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“…This suggests that C3 biosynthesis may be dependent upon molecular mechanisms specific and non-specific for IBD, as complements are major factors in innate immune responses against a huge number of antigens. An increasing number of studies have focused upon the role of Th17 cells in the pathogenesis of IBD [8,10,[12][13][14]47], due to its unique differentiation processes under the stimulus of transforming growth factor (TGF)-b and IL-6 [3][4][5][6][7][8][9][10][11]. Th17 cells develop from naive T lymphocytes through distinct pathways from classical Th1 and Th2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an increasing number of studies focused upon a critical role of T helper type 17 (Th17) cells and interleukin (IL)-17 in the pathogenesis of IBD [3][4][5][6][7][8][9][10][11]. Th17 cells are novel subsets of CD4 + T cells, characterized by IL-17 secretion and the expression of the transcription factor retinoic acid-related orphan receptor (ROR)g [8,10,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease

Sugihara

Kobori

Imaeda

et al. 2010

Clinical and Experimental Immunology

109

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Section: Discussionmentioning

confidence: 88%

“…Thus, aggravation of clinical symptoms in GFAP-Cre FasL fl/fl mice correlated with an increased IL-17 mRNA transcription, indicating that this cytokine was decisive for the more severe and persisting EAE in these mice. IL-23, which drives IL-17 polarization of CD4 + T cells was not increased in the CNS of GFAP-Cre FasL fl/fl mice, which fits to the important role of IL-23 for Th17 polarization in lymphatic organs [31].Astrocytes play both positive and negative roles in the pathogenesis and development of EAE [32]. As part of the blood-brain barrier, early chemokine release of astrocytes contributes to the recruitment of autoimmune CD4 + T cells to the CNS [33].…”

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confidence: 91%

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

et al. 2012

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In T-cell-mediated autoimmune diseases of the CNS, apoptosis of FasKeywords: Autoimmunity r Astrocytes r EAE r FasL Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction EAE is a widely used animal model to study MS, an inflammatory demyelinating disease mediated by accumulation of T lymphocytes and macrophages in the CNS [1,2]. EAE can be induced by either active immunization with myelin Ags including myelin oligodendrocyte glycoprotein (MOG) peptide or passive transfer of myelin-reactive CD4 + T cells, which are both initiators and Correspondence: Prof. Dirk Schlüter e-mail: dirk.schlueter@med.ovgu.de effectors of EAE. Among CD4 + T lymphocytes, GM-CSF-producing CD4 + T cells, IFN-γ-secreting Th1 cells, and IL-17-secreting Th17 cells have been identified as the most important mediators in the immunopathogenesis of EAE [3][4][5][6] and all of them can induce EAE independently, although recent studies point to an essential role of GM-CSF-producing CD4 + T cells, which can induce EAE independent of . Infiltrating T lymphocytes trigger an inflammatory response in the CNS culminating in demyelination and axonal damage clinically resulting in paralysis [8]. Correspondingly, recovery from EAE requires termination of inflammation and the induction of T-cell apoptosis in the CNS [9].www.eji-journal.eu 116Xu Wang et al. Eur. J. Immunol. 2013. 43: 115-124 Fas ligand (FasL; CD95L), a cytotoxic cytokine belonging to the TNF superfamily, acts through Fas, a death receptor of the TNFR superfamily, to induce programed cell death via caspase signaling [10]. Local expression of FasL in immunoprivileged organs including eyes, testis, and placenta is essential for deletion of infiltrating inflammatory cells [11][12][13]. Fas/FasL interaction is of particular importance for homeostasis of the immune system and its dysregulation has been implicated in various autoimmune diseases. Mice carrying autosomal recessive mutations in the Fas (lpr) and FasL (gld) genes develop a spontaneous autoimmune syndrome similar to human systemic lupus erythematosus [14,15]. Fas and FasL are also involved in the pathogenesis of EAE, as EAE is dramatically ameliorated in lpr and gld mice in terms of disease incidence and mean clinical score [16]. Intrathecal infusion of recombinant FasL induces apoptosis of CNS-infiltrating inflammatory cells, including T cells and macrophages, but does not exert cytotoxicity against CNS-resident cells, resulting in mitigated EAE manifestations [17].Elimination of infiltrating T cells in the CNS by Fas/FasLmediated apoptosis is crucial for resolution of EAE [9,18,19], since FasL-deficient gld recipients develop prolonged EAE after adoptive transfer of myelin basic protein-reactive WT Fas + T lymphocytes [20]. The CNS-resident cell population which induces apoptosis of CD4 + T cells in EAE still remains to be identified. We hypothesize that astrocytes, which constitutively express FasL, may play a key role given that FasL-expressing astrocytes a...

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IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease

Abstract: IL23 may play important roles in controlling the differential Th1/Th17 balance in both UC and CD, although Th17 cells may exist in both diseases.

Cited by 491 publications

References 47 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

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