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Expression of IL-24, an Activator of the JAK1/STAT3/SOCS3 Cascade, Is Enhanced in Inflammatory Bowel Disease

Akira Andoh^1,2,*, Makoto Shioya^1,*, Atsushi Nishida^*, Shigeki Bamba^*, Tomoyuki Tsujikawa^*, Shokei Kim-Mitsuyama and Yoshihide Fujiyama^*

^* Department of Medicine, Shiga University of Medical Science, Otsu, Japan; and Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

IL-24 is a member of the IL-10 family of cytokines. In this study, we investigated IL-24 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-24 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-24 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-24 mRNA and protein expression was determined by real-time PCR and ELISA, respectively. AP-1 and C/EBP DNA-binding activity and IL-24 promoter activity were assessed by EMSA analysis and a reporter gene assay, respectively. IL-24 mRNA expression was significantly elevated in active lesions from patients who have ulcerative colitis and Crohn’s disease. Colonic SEMFs were identified as a major source of IL-24 in the mucosa. IL-1β, but not IL-17A, TNF-, or IFN-, significantly enhanced IL-24 mRNA and protein expression in isolated colonic SEMFs. The IL-1β-induced IL-24 mRNA expression was mediated by the activation of the transcription factors, AP-1 and C/EBP-β. Induction of IL-24 mRNA stabilization was also involved in the effects of IL-1β. IL-24 induced JAK1/STAT-3 phosphorylation and SOCS3 expression in HT-29 colonic epithelial cells. IL-24 did not modulate the proliferation of HT-29 cells, but significantly increased the mRNA expression of membrane-bound mucins (MUC1, MUC3, and MUC4). IL-24 derived from colonic SEMFs acts on colonic epithelial cells to elicit JAK1/STAT-3 activation and the expression of SOCS3 and mucins, supporting their suppressive effects on mucosal inflammation in IBD.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A.A. and M.S. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Akira Andoh, Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu 520-2192, Japan. E-mail address: andoh{at}belle.shiga-med.ac.jp

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; SEMF, subepithelial myofibroblast; UC, ulcerative colitis; CD, Crohn’s disease; siRNA, small interfering RNA; SMA, smooth muscle actin; SOCS, suppressors of cytokine signaling.