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

Akira Andoh,Atsushi Nishida,Shokei Kim-Mitsuyama,Shigeki Bamba,Tomoyuki Tsujikawa,Makoto Shioya,Yoshihide Fujiyama

doi:10.4049/jimmunol.0804169

Akira Andoh, Atsushi Nishida + Show 5 more

Open Access

https://doi.org/10.4049/jimmunol.0804169

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Abstract

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-1beta, but not IL-17A, TNF-alpha, or IFN-gamma, significantly enhanced IL-24 mRNA and protein expression in isolated colonic SEMFs. The IL-1beta-induced IL-24 mRNA expression was mediated by the activation of the transcription factors, AP-1 and C/EBP-beta. Induction of IL-24 mRNA stabilization was also involved in the effects of IL-1beta. 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.

Highlights

Inflammatory bowel disease (IBD),3 ulcerative colitis (UC), and Crohn’s disease (CD) are characterized by chronic inflammation, in which a dysfunction of the host immune response against common Ags such as dietary factors or bacteria may be involved [1, 2]
To investigate the role of MAPKs in the IL-1␤-induced IL-24 mRNA expression in subepithelial myofibroblasts (SEMFs), we evaluated the effects of p42/44 MAPK inhibitors (PD98059 and U0216) [42, 43], a p38 MAPK inhibitor (SB203580) [44], and a JNK inhibitor (JNK Inhibitor I) [45]
We demonstrated some novel findings concerning the expression and function of IL-24: 1) IL-24 expression is increased in the inflamed mucosa from inflammatory bowel disease (IBD) patients, and colonic SEMFs are a major local source; 2)

Summary

Introduction

Inflammatory bowel disease (IBD),3 ulcerative colitis (UC), and Crohn’s disease (CD) are characterized by chronic inflammation, in which a dysfunction of the host immune response against common Ags such as dietary factors or bacteria may be involved [1, 2]. Based on the in vivo expression of IL-24 in the inflamed IBD mucosa, we examined IL-24 expression in isolated human colonic SEMFs. Colonic SEMFs were stimulated with various cytokines and LPS for 12 h, and the IL-24 mRNA expression was determined by real-time PCR (Fig. 3A, top blot). In the colonic epithelial cell lines (HT-29, SW480, and Caco-2), IL-1␤ failed to induce IL-24 mRNA expression (Fig. 3B).

Results

Conclusion