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IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators¹

Department of Internal Medicine, Shiga University of Medical Science, Seta Tukinowa, Otsu, Japan

There is increasing evidence that IL-6 plays an important role in the pathophysiology of acute pancreatitis via its broad proinflammatory actions. To identify the local biosynthetic site for IL-6 in human pancreas, we investigated IL-6 secretion in human pancreatic periacinar myofibroblasts. IL-6 secretion was determined by ELISA and Northern blotting. The activation of NF-B was assessed by EMSA. The activation of mitogen-activated protein kinase (MAPK) was assessed by immunoblotting. IL-6 secretion was rapidly induced by IL-17, IL-1, and TNF-. EMSAs demonstrated that IL-17, IL-1, and TNF- induced NF-B activation within 1.5 h after stimulation, and a blockade of NF-B activation by the pyrrolidine derivative of dithiocarbamate and tosyl-phe-chloromethylketone markedly reduced the IL-17-, IL-1-, or TNF--induced IL-6 gene expression. Furthermore, IL-17, IL-1, and TNF- induced a rapid activation of extracellular signal-related kinase p42/44 and p38 MAPKs, and specific MAPK inhibitors (SB203580, PD98059, and U0216) significantly reduced IL-17-, IL-1-, or TNF--induced IL-6 secretion, indicating the role of MAPKs in the induction of IL-6. The combination of either IL-17 plus IL-1 or IL-17 plus TNF- enhanced IL-6 secretion and IL-6 mRNA expression; in particular, the effects of IL-17 plus TNF- were much stronger than those induced by IL-17 plus IL-1. TNF--induced IL-6 mRNA degraded rapidly at any concentrations, and the combination of IL-17 and TNF- markedly enhanced IL-6 mRNA stability. This indicates that the effects of IL-17 plus TNF- were regulated at the post-transcriptional level. In conclusion, pancreatic periacinar myofibroblasts secreted a large amount of IL-6 in response to proinflammatory cytokines. These cells might play an important role in the pathogenesis of acute pancreatitis via IL-6 secretion.

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