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IL-9 promotes the pathogenesis of ulcerative colitis through STAT3/SOCS3 signaling.

ABSTRACT: Ulcerative colitis (UC) is a chronic condition in which the overreacting immune system may play an important role. It has been confirmed that the interleukin (IL) 9 (IL-9) participates in the pathogenesis of UC but the molecular mechanism is not fully illustrated. Here, we show that levels of peripheral blood cytokines IL-9, IL-8, IL-10, IL-6, IL-1?, IL-12, and tumor necrosis factor (TNF) were higher in patients with UC than normal control, and serum and local IL-9 levels were positively correlated with the disease activity grade. Moreover, IL-9 stimulation inhibited suppressor of cytokine signaling 3 (SOCS3) expression and wound healing ability in colonic epithelial cells and promoted the phosphorylation level of signal transducers and activators of transcription 3 (STAT3). And IL-9 stimulation promoted claudin-2 expression while inhibited claudin-3 and occludin expression. Furthermore, SOCS3 overexpression rescued the IL-9-induced effects. Altogether, IL-9 participates in the pathogenesis of UC through STAT3/SOCS3 signaling pathway and has the potential to serve as a possible therapeutic candidate in patients with UC.

SUBMITTER: Tian L

PROVIDER: S-EPMC6259019 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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IL-9 promotes the pathogenesis of ulcerative colitis through STAT3/SOCS3 signaling.

Tian Linglin L Li Yuan Y Zhang Jian J Chang Ruqi R Li Jianhong J Huo Lijuan L Huo Lijuan L

Bioscience reports 20181128 6

Ulcerative colitis (UC) is a chronic condition in which the overreacting immune system may play an important role. It has been confirmed that the interleukin (IL) 9 (IL-9) participates in the pathogenesis of UC but the molecular mechanism is not fully illustrated. Here, we show that levels of peripheral blood cytokines IL-9, IL-8, IL-10, IL-6, IL-1β, IL-12, and tumor necrosis factor (TNF) were higher in patients with UC than normal control, and serum and local IL-9 levels were positively correla ...[more]

PMID: 30369485

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Project description:Ulcerative colitis (UC) is a chronic disease associated with long periods of quiescent disease followed by fulminant exacerbation. Imminent relapse in UC is associated with high mucosal expression of suppressor of cytokine signaling 3 (SOCS3); hence, knowledge of the mechanisms driving mucosal SOCS3 expression may provide important clues as to rational therapy. Thus, here we aim to characterize the molecular forces driving SOCS3 expression in the mucosal compartment, focusing on druggable pathways. The colon epithelial cell line Caco-2 was stimulated with interferon (IFN)-?, interleukin (IL)-4 or prostaglandin E(2) (PGE(2)) to allow correlations between SOCS3 expression with signal transducer and activator of transcription 1 (STAT1), STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling, respectively. The physiological relevance of the findings obtained was assessed by immunohistochemical staining for the activated forms of STAT1, STAT6, protein kinase A (PKA)-C? and cAMP response element-binding protein (CREB) in biopsies from inactive UC patients and controls. Stimulation with IFN-?, IL-4 or PGE(2) induced activation of STAT1, STAT6 and cAMP, respectively, in colonic cells, without any signs of concomitant STAT3 activation. Forced activation of all these signaling pathways was sufficient for SOCS3 expression. Biopsies from patients with inactive UC showed significant increase of phosphorylated STAT1 (p-STAT1) (p < 0.0001), p-STAT6 (p = 0.0001), p-PKA-C? (p = 0.0003) and p-CREB (p = 0.0025) expression compared with controls. STAT3-independent SOCS3 induction in inactive UC involves multiple proinflammatory signaling pathways and contradicts the usefulness of pathway-specific antiinflammatory drugs for preventing relapse. Our findings suggest that broad-spectrum antiinflammatory drugs are essential to counteract increases in SOCS3 expression and exacerbation of disease. Our results highlight the multifactorial nature of the factors that cause exacerbation in UC.

Dataset Information

IL-9 promotes the pathogenesis of ulcerative colitis through STAT3/SOCS3 signaling.

Publications

IL-9 promotes the pathogenesis of ulcerative colitis through STAT3/SOCS3 signaling.

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