IL-25 Downregulates Th1/Th17 Immune Response in an IL-10–Dependent Manner in Inflammatory Bowel Disease

Su, Jie; Chen, Tengfei; Ji, Xin‐Ying; Liu, Chunlu; Yadav, Praveen Kumar; Wu, Rui; Yang, Ping‐Chang; Liu, Zhanju

doi:10.1097/mib.0b013e3182802a76

Cited by 92 publications

(85 citation statements)

References 35 publications

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“…28 Interleukin-2 is the key cytokine supporting the survival and function of Treg cells, 29 and TGF-β and IL-2 can also be crucial in 'reprogramming' Th2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drive the differentiation of Th9 cells directly. 3 In colonic mucosa, IL-25 (IL-17E), which has been experimentally found to be involved in this switch, can downregulate Th1/Th17 immune responses in an IL-10-dependent manner, 30 and it has also been found that the IL-10 31 and IL-17 families 22 are increased in the colonic mucosa of patients with active UC. It is therefore possible that, IL-9 can be produced by Th17 or modified Th2 cells in a Th1 habitus in the presence of TCR stimulation in vivo and is detectable in the peripheral blood of IBD patients.…”

Section: Discussionmentioning

confidence: 99%

Significance of serum Il-9 levels in inflammatory bowel disease

Defendenti

Sarzi-Puttini

Saibeni³

et al. 2015

Int J Immunopathol Pharmacol

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IL-9, which may be an inflammatory or regulatory cytokine, can be experimentally produced in a Th17 or modified Th2 context in the presence of T cell receptor (TCR) stimulation. The primary aim of this study was to measure serum IL-9 levels in patients with inflammatory bowel disease (IBD), and evaluate their relationships with the patients' clinical characteristics. The secondary aim was to determine the levels of interferon-γ (IFN (interferon)-γ), Th2 cytokines (IL-4, IL-5 and IL-13), and IL-6 in order to clarify the context of detectable peripheral cytokines in which IL-9 is produced.Venous blood samples of 43 IBD patients (20 with Crohn's disease [CD] and 23 with ulcerative colitis [UC]) were analysed by means of quantitative enzyme-linked immunosorbent assays using purified anti-human IL-4, IL-5, IL-13, IFN-γ, IL-9 and IL-6 antibodies, and the laboratory findings were statistically correlated with their clinical expression.None of the patients showed the peripheral presence of IL-4, IL-5 and IL-13. Forty (93%) were positive for IFN-γ, thus confirming the presence of Th1 in both UC and CD, and IFN-γ levels correlated with disease activity (P = 0.045). Eighteen patients (41%) were positive for IL-9, which was associated with a severe prognosis (P <0.001), and 72.2% of the IL-9-positive patients were also IL-6 positive. There was a significant correlation between disease severity and IL-9 in the CD patients (P <0.001), but not in the UC patients (P = 0.1).Our findings confirm the presence of common Th1 cytokines in UC and CD. However the IL-9 positivity indicates the presence of an alternative population of T cells that respond to antigen stimulation and condition the prognosis of IBD. The fact that the same serum IL-9 levels were differentially associated with clinical measures of CD and UC activity suggest that the same cytokine can be produced in different contexts.

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Section: Discussionmentioning

confidence: 99%

Significance of serum Il-9 levels in inflammatory bowel disease

Defendenti

Sarzi-Puttini

Saibeni³

et al. 2015

Int J Immunopathol Pharmacol

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“…Recently, Im et al reported that IL-17C was upregulated in the intestine of IBD patients, although only significantly so in CD patients [44]. These same investigators implied that IL-17C could play a proinflammatory role in IBD [45]. In contrast, other investigators suggested a protective role for IL-17C against DSS-induced colitis in mice [43,46].…”

Section: Il-17 Inhibition and Ibd mentioning

confidence: 94%

Inhibition of IL-17 as a Pharmacological Approach for IBD

Fitzpatrick

2013

International Reviews of Immunology

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Several experimental approaches have been utilized, in order to critically examine the roles of IL-17 family members in intestinal inflammation. These approaches have included: (1) the use of IL-17A and IL-17F-deficient mice, (2) specific antibodies directed against IL-17, (3) an IL-17 vaccine, (4) methods to block the IL-17 receptor and (5) small-molecule inhibitors of IL-17. Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease (IBD), using specific strains of IL-17-deficient mice. This paper will review the preclinical results using various pharmacological approaches [specific IL-17 antibodies, an IL-17 receptor fusion protein, IL-12/IL-23 p40 subunit and IL-17 vaccine approaches, as well as a small molecule inhibitor (Vidofludimus)] to inhibit IL-17 in animal models of IBD. Recent clinical results in patients with IBD will also be discussed for Secukinumab (an IL-17A antibody), Brodalumab (an IL-17 receptor antibody) and two small-molecule drugs (Vidofludimus and Tofacitinib), which inhibit IL-17 as part of their overall pharmacological profiles. This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti-IL-17 drugs, as related to drug pharmacodynamics, IL-17 receptor subtypes and other pertinent factors. Finally, future pharmacological approaches of interest will be discussed, such as: (1) Retinoic acid receptor-related orphan nuclear receptor gamma t (Rorγt) antagonists, (2) Retinoic acid receptor alpha (RARα) antagonists, (3) Pim-1 kinase inhibitors and (4) Dual small-molecule inhibitors of NF-κB and STAT3, like synthetic triterpenoids.

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“…[142][143][144] Mechanistically, the anti-colitic effect mediated by IL-17E is probably dependent on the activation of anti-inflammatory alternatively activated macrophages (AAMs) and the inhibition of CD4 + T-cell activation and their differentiation into inflammatory Th1/Th17 cells in the colon. 141,142,144,145 Recombinant IL-17E even ameliorates oxazolone-induced type 2 colitis, indicating that IL-17E has a broad anti-inflammatory effect in the colon rather than selectively suppressing Th1/Th17 cytokine production. 144 A recent study showed that IL-17E was produced by intestinal epithelial cells during acute colitis and that mice deficient in IL-17E were protected from DSS-induced colitis.…”

Section: Il-17dmentioning

confidence: 99%

“…Il-17E expression is downregulated in inflamed colons from IBD patients and DSS-treated mice. 141,142 In vivo delivery of recombinant IL-17E inhibits the development of DSS-, 2,4,6-trinitrobenzenesulphonic acid (TNBS)-, or peptidoglycan (PGN)-induced acute colitis in mice. [142][143][144] Mechanistically, the anti-colitic effect mediated by IL-17E is probably dependent on the activation of anti-inflammatory alternatively activated macrophages (AAMs) and the inhibition of CD4 + T-cell activation and their differentiation into inflammatory Th1/Th17 cells in the colon.…”

Section: Il-17dmentioning

confidence: 99%

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

et al. 2016

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The mucosal immune system serves as our front-line defense against pathogens. It also tightly maintains immune tolerance to self-symbiotic bacteria, which are usually called commensals. Sensing both types of microorganisms is modulated by signalling primarily through various pattern-recognition receptors (PRRs) on barrier epithelial cells or immune cells. After sensing, proinflammatory molecules such as cytokines are released by these cells to mediate either defensive or tolerant responses. The interleukin-17 (IL-17) family members belong to a newly characterized cytokine subset that is critical for the maintenance of mucosal homeostasis. In this review, we will summarize recent progress on the diverse functions and signals of this family of cytokines at different mucosal edges.

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IL-25 Downregulates Th1/Th17 Immune Response in an IL-10–Dependent Manner in Inflammatory Bowel Disease

Cited by 92 publications

References 35 publications

Significance of serum Il-9 levels in inflammatory bowel disease

Significance of serum Il-9 levels in inflammatory bowel disease

Inhibition of IL-17 as a Pharmacological Approach for IBD

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

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