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

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-1β, but not IL-17A, TNF-α, or IFN-γ, 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 increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease

“…In addition, this is the first clinical report demonstrating a strong correlation between increased C3 and IL-17 mRNA expression in the IBD mucosa. The behaviour of C3 mRNA expression in the IBD mucosa was different from other factors described previously [4,45,46]. Elevation of C3 mRNA expression was observed not only in active IBD mucosa but also in infectious colitis, although many factors have been reported to be elevated specifically in IBD mucosa [4,[45][46][47].…”

“…The behaviour of C3 mRNA expression in the IBD mucosa was different from other factors described previously [4,45,46]. Elevation of C3 mRNA expression was observed not only in active IBD mucosa but also in infectious colitis, although many factors have been reported to be elevated specifically in IBD mucosa [4,[45][46][47]. This suggests that C3 biosynthesis may be dependent upon molecular mechanisms specific and non-specific for IBD, as complements are major factors in innate immune responses against a huge number of antigens.…”

Involvement of the IL-22/REG Iα axis in ulcerative colitis

“…29,30 Interestingly, IL-22 is thought to be produced by immune cells such as Th17, NK, 31,32 anti-bacterial peptides (b-defensin, calgranulins), 33,34 and mucin (MUC1, -3, -10, and -13). 35,36 In this study, we examined whether IL-22 stimulation is responsible for REG Ia overexpression in the colonic epithelium in UC mucosa, because in several gene tip analyses REG Ia has been proven to be a distinctly upregulated gene in the colonic epithelium of patients with UC. 23,24 Moreover, we found using microarray analysis that REG Ia is also a novel upregulated gene in a colon cancer cell line stimulated with IL-22 (data not shown).…”

Stat6 and c-Jun Mediate Th2 Cell-Specific IL-24 Gene Expression

“…In the human immune system, certain stimuli promote secretion of IL-24 by PBMCs, preferably monocytes and T and B cells (15,16). IL-24 is produced not only by activated immune cells but also to a similar extent by nonimmune cells such as cultured melanocytes (10), dermal keratinocytes (17), and IL-1-stimulated human colonic subepithelial myofibroblasts (18). IL-24 expression also has been reported in affected joints of rheumatoid arthritis patients (19) and is involved in the immunopathology of psoriasis (17,20) at the edge of excisional skin wounds (21) and in active lesions from patients who have ulcerative colitis and Crohn's disease (18).…”

“…IL-24 is produced not only by activated immune cells but also to a similar extent by nonimmune cells such as cultured melanocytes (10), dermal keratinocytes (17), and IL-1-stimulated human colonic subepithelial myofibroblasts (18). IL-24 expression also has been reported in affected joints of rheumatoid arthritis patients (19) and is involved in the immunopathology of psoriasis (17,20) at the edge of excisional skin wounds (21) and in active lesions from patients who have ulcerative colitis and Crohn's disease (18). IL-24 inhibits differentiation of germinal center B cells into mature plasma cells and promotes their maturation toward the memory B cell pathway (22).…”