Objective: Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 binds to a complex of ST2L/IL-1 receptor accessory protein (IL-1RAcP). To define the role of IL-33 in fibrogenesis in the pancreas, the expression of IL-33, ST2L and IL-1RAcP was examined in chronic pancreatitis tissues. The effects of IL-33 on the functions of human pancreatic myofibroblasts were also investigated.
Methods: Tissue samples were obtained surgically. The expression of IL-33, ST2L and IL-1RAcP was evaluated by standard immunohistochemical procedures. Messenger RNA expression for IL-33, ST2L and IL-1RAcP was analyzed by Northern blotting and real-time PCR analyses, and protein expression was assessed by Western blotting and ELISA. Cell proliferation and migration were assessed by a [3H]thymidine incorporation assay and the modified Boyden chamber assay, respectively.
Results: IL-33, ST2L and IL-1RAcP were expressed by α-SMA-positive myofibroblasts in the fibrosis of chronic pancreatitis. In human pancreatic myofibroblasts, IL-33 was weakly immunoexpressed without any stimuli, and this was markedly enhanced by IL-1β], TNF-α\ and lipopolysaccharide (LPS) via the mitogen-activated protein kinase (MAPK)-dependent AP-1 activation pathway. ST2L mRNA was weakly detected in un-stimulated cells, and IL-4 and IFN-γ strongly enhanced ST2L expression via STAT6- and STAT1 signaling, respectively. IL-33 rapidly induced the phosphorylation of MAPKs and IκBα, and enhanced the expression of inflammatory mediators (IL-6, IL-8, IP-10, Gro-α, Gro-β and MCP-1) in IL-4- or IFN-γ-pretreated cells. IL-33 stimulated the proliferation and migration of pancreatic myofibroblasts.
Conclusions: IL-33 and its receptor complex (ST2L and IL-1RAcP) are a novel signaling system which may play an important role in the pathogenesis of chronic pancreatitis.
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