OBJECTIVES: Interleukin-36 (IL-36) is a recently described proinflammatory cytokine, characterized by the induction of inflammatory mediators. In the present study, we investigated the biological activity and the signal transduction of IL-36α in human pancreatic myofibroblasts. METHODS: The mRNA and protein expression of inflammatory mediators was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of IL-36α and its receptor in the pancreatic tissue was evaluated using immunohistochemical technique. Intracellular signaling pathways were evaluated using immunoblotting and specific small interference RNA-transfected cells. RESULTS: Interleukin-36α and its receptor complex IL-36R/IL-1RAcP were detected in fibrotic tissue of chronic pancreatitis. Interleukin-36α dose- and time-dependently induced the mRNA expression and protein secretion of CXCL1, CXCL8, MMP-1, and MMP-3 from human pancreatic myofibroblasts. Interleukin-36α assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex. Furthermore, IL-36α induced the phosphorylation of mitogen-activated protein kinases and the activation of nuclear factor κB and activator protein 1. Mitogen-activated protein kinase inhibitors and small interference RNAs specific for nuclear factor κB and activator protein 1 significantly suppressed the protein secretion of inflammatory mediators induced by IL-36α stimulation. CONCLUSIONS: It was suggested that IL-36α plays an important role in the pathophysiology of inflammation and fibrosis in the pancreas via an autocrine function.
OBJECTIVES: Interleukin-36 (IL-36) is a recently described proinflammatory cytokine, characterized by the induction of inflammatory mediators. In the present study, we investigated the biological activity and the signal transduction of IL-36α in humanpancreatic myofibroblasts. METHODS: The mRNA and protein expression of inflammatory mediators was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of IL-36α and its receptor in the pancreatic tissue was evaluated using immunohistochemical technique. Intracellular signaling pathways were evaluated using immunoblotting and specific small interference RNA-transfected cells. RESULTS: Interleukin-36α and its receptor complex IL-36R/IL-1RAcP were detected in fibrotic tissue of chronic pancreatitis. Interleukin-36α dose- and time-dependently induced the mRNA expression and protein secretion of CXCL1, CXCL8, MMP-1, and MMP-3 from humanpancreatic myofibroblasts. Interleukin-36α assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex. Furthermore, IL-36α induced the phosphorylation of mitogen-activated protein kinases and the activation of nuclear factor κB and activator protein 1. Mitogen-activated protein kinase inhibitors and small interference RNAs specific for nuclear factor κB and activator protein 1 significantly suppressed the protein secretion of inflammatory mediators induced by IL-36α stimulation. CONCLUSIONS: It was suggested that IL-36α plays an important role in the pathophysiology of inflammation and fibrosis in the pancreas via an autocrine function.
Authors: Michael Elias; Shuai Zhao; Hongnga T Le; Jie Wang; Markus F Neurath; Clemens Neufert; Claudio Fiocchi; Florian Rieder Journal: J Clin Invest Date: 2021-01-19 Impact factor: 14.808
Authors: Jie Wang; Sinan Lin; Jonathan Mark Brown; David van Wagoner; Claudio Fiocchi; Florian Rieder Journal: Immunol Rev Date: 2021-05-16 Impact factor: 10.983