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Noncanonical STAT3 activation regulates excess TGF-?1 and collagen I expression in muscle of stricturing Crohn's disease.

ABSTRACT: Increased TGF-?1 and TGF-?1-dependent Collagen I production in intestinal mesenchymal cells result in fibrosis in patients with Montreal B2 fibrostenotic Crohn's disease. Numerous cytokines, including IL-6, are produced by activated mesenchymal cells themselves and activate STAT3. The aim of the current study was to determine the mechanisms by which STAT-3 activation might result in intestinal fibrosis. Cytokine levels were measured by ELISA. STAT3 and suppressor of cytokine signaling 3 protein levels were measured by immunoblot, STAT3-TGFB1 DNA-binding activity by chromatin immunoprecipitation, and TGFB1 transcriptional activity by luciferase reporter assay. TGF-?1 (TGFB1), Collagen1?1, and connective tissue growth factor (CTGF) gene expression was measured by quantitative RT-PCR. The role of STAT3 activation was determined using STAT3 inhibitor, Stattic, and by transfection of STAT3 mutants. Autocrine production of cytokines was increased in muscle cells of B2 phenotype patients from strictures and normal intestine in the same patient and compared with other Crohn's phenotypes, ulcerative colitis, and non-Crohn's patients. A unique pattern of STAT3 phosphorylation emerged: high STAT3(S727) and low STAT3(Y705) in strictures and the opposite in unaffected intestine. TGFB1 transcriptional activity was regulated by phospho-STAT3(S727) and was decreased by Stattic or dominant-negative STAT3(S727A). TGF-?1, COL1A1, and CTGF expression was inhibited by Stattic or dominant-negative STAT3(S727A). Treatment of normal muscle cells with IL-6 or expression of constitutively active STAT3(S727E) phenocopied muscle cells from strictured intestine. Neutralization of autocrine IL-6 reversed STAT3 phosphorylation and normalized expression of TGF-?1 in strictured intestinal muscle. The ability of Stattic to improve development of fibrosis was confirmed in mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis. We observed a unique phospho-STAT3(S727) response in patients with Montreal B2 Crohn's disease, particularly in response to IL-6 leading to increased TGF-?1, collagen, and CTGF production in ileal strictures.

SUBMITTER: Li C

PROVIDER: S-EPMC4369432 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Noncanonical STAT3 activation regulates excess TGF-β1 and collagen I expression in muscle of stricturing Crohn's disease.

Li Chao C Iness Audra A Yoon Jennifer J Grider John R JR Murthy Karnam S KS Kellum John M JM Kuemmerle John F JF

Journal of immunology (Baltimore, Md. : 1950) 20150304 7

Increased TGF-β1 and TGF-β1-dependent Collagen I production in intestinal mesenchymal cells result in fibrosis in patients with Montreal B2 fibrostenotic Crohn's disease. Numerous cytokines, including IL-6, are produced by activated mesenchymal cells themselves and activate STAT3. The aim of the current study was to determine the mechanisms by which STAT-3 activation might result in intestinal fibrosis. Cytokine levels were measured by ELISA. STAT3 and suppressor of cytokine signaling 3 protein ...[more]

PMID: 25740948

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Project description:BACKGROUND & AIMS:It is a challenge to predict how patients with small bowel Crohn's disease (CD) will respond to intensified medical therapy. We aimed to identify factors that predicted surgery within 2 years of hospitalization for CD, to guide medical versus surgical management decisions. METHODS:We performed a retrospective review of adults hospitalized for small bowel CD from 2004 through 2012 at a single academic referral center. Subjects underwent abdominal computed tomography or magnetic resonance imaging within 3 weeks of hospitalization. Imaging characteristics of small bowel dilation, bowel wall thickness, and disease activity were assessed by a single, blinded radiologist. Multivariate analysis by Cox proportional hazards regression techniques was used to generate a prediction model of intestinal resection within 2 years. RESULTS:A total of 221 subjects met selection criteria, with 32.6% undergoing surgery within 2 years of index admission. Bivariate analysis showed high-dose steroid use (>40 mg), ongoing treatment with anti-tumor necrosis factor agents at admission, platelet count, platelet:albumin ratio, small bowel dilation (?35 mm), and bowel wall thickness to predict surgery (P ? .01). Multivariate modeling demonstrated small bowel dilation >35 mm (hazard ratio, 2.92; 95% confidence interval, 1.73-4.94) and a platelet:albumin ratio ?125 (hazard ratio, 2.13; 95% confidence interval, 1.15-3.95) to predict surgery. Treatment with anti-tumor necrosis factor agents at admission conferred a nonsignificant increased trend for risk of surgery (hazard ratio, 1.61; 95% confidence interval, 0.994-2.65). CONCLUSIONS:Small bowel dilation >35 mm and high platelet:albumin ratios are independent and synergistic risk factors for future surgery in patients with structuring small bowel CD. Platelet:albumin ratios may capture the relationship between acute inflammation and cumulative damage and serve as markers of intestinal disease that cannot be salvaged with medical therapy.

Dataset Information

Noncanonical STAT3 activation regulates excess TGF-?1 and collagen I expression in muscle of stricturing Crohn's disease.

Publications

Noncanonical STAT3 activation regulates excess TGF-β1 and collagen I expression in muscle of stricturing Crohn's disease.

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