Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease.
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.
Andoh
Akira
A
Department of Medicine, Shiga University of Medical Science, Otsu, Japan. andoh@belle.shiga-med.ac.jp
Shioya
Makoto
M
Nishida
Atsushi
A
Bamba
Shigeki
S
Tsujikawa
Tomoyuki
T
Kim-Mitsuyama
Shokei
S
Fujiyama
Yoshihide
Y
D018938:Caco-2 Cells; D002460:Cell Line; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053613:Janus Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D009077:Mucins / Q000096:biosynthesis / Q000235:genetics; D009130:Muscle, Smooth / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology; D000099180:Interleukin-24
D007378:Interleukins; D053613:Janus Kinase 1; D009077:Mucins; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000099180:Interleukin-24; C106644:SOCS3 protein, human; C494086:STAT3 protein, human; C507904:JAK1 protein, human