Abstract
Interleukin (IL)-36 cytokines are recently reported member of the IL-1 cytokine family. However, there is little information regarding the association between IL-36 cytokines and gut inflammation. In the present study, we investigated the biological activity of IL-36α and IL-36γ using human colonic subepithelial myofibroblasts (SEMFs). The mRNA expression and the protein expression of target molecules in SEMFs were evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The intracellular signaling of IL-36 cytokines was analyzed using Western blot analysis and small interfering RNAs (siRNAs) specific for MyD88 adaptor proteins (MyD88 and IRAK1) and NF-κB p65. IL-36α and IL-36γ significantly enhanced the secretion of IL-6 and CXC chemokines (CXCL1, CXCL2, and CXCL8) by SEMFs. The combination of IL-36α/γ and IL-17A or of IL-36α/γ and tumor necrosis factor-α showed a synergistic effect on the induction of IL-6 and CXC chemokines. The mRNA expression of proinflammatory mediators induced by IL-36α and/or IL-36γ was significantly suppressed by transfection of siRNA for MyD88 or IRAK1. Both inhibitors of mitogen activated protein kinases and siRNAs specific for NF-κBp65 significantly reduced the expression of IL-6 and CXC chemokines induced by IL-36α and/or IL-36γ. These results suggest that IL-36α and IL-36γ contribute to gut inflammation through the induction of proinflammatory mediators.
Highlights
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic inflammation in the gastrointestinal tract [1,2,3]
To investigate the function of IL-36 cytokines in human colonic subepithelial myofibroblasts (SEMFs), the cells were stimulated with IL-36α (100 ng/ml) or IL-36γ (100 ng/ml) for 24 h, and the mRNA expression of IL-6 and CXC chemokines (CXCL1, CXCL2, and CXCL8) was evaluated using real-time polymerase chain reaction (PCR)
B, both IL-36α and IL-36γ induced a significant increase in the mRNA and protein expression of these proinflammatory mediators compared to the medium control. These results indicate that IL-36α and IL-36γ are strong inducers of proinflammatory mediators in human colonic SEMFs
Summary
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic inflammation in the gastrointestinal tract [1,2,3]. A dysfunction of the host immune response to dietary factors and/or the gut microbiota has been reported to play an important role in the pathogenesis [4,5,6,7,8,9]. Recent studies showed that IL-36 cytokines play an important role in the pathogenesis of psoriasis [16,17,18,19,20], rheumatoid arthritis [21,22,23] or pulmonary disease [24, 25]. There are few reports regarding the function of IL-36 in gut inflammation. Interleukin (IL)-36 cytokines are recently reported member of the IL-1 cytokine family. There is little information regarding the association between IL-36 cytokines and gut inflammation. We investigated the biological activity of IL-36α and IL-36γ using human colonic subepithelial myofibroblasts (SEMFs)
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