IL-6 secretion by human pancreatic periacinar myofibroblasts in response to inflammatory mediators.
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-kappaB 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-1beta, and TNF-alpha. EMSAs demonstrated that IL-17, IL-1beta, and TNF-alpha induced NF-kappaB activation within 1.5 h after stimulation, and a blockade of NF-kappaB activation by the pyrrolidine derivative of dithiocarbamate and tosyl-phe-chloromethylketone markedly reduced the IL-17-, IL-1beta-, or TNF-alpha-induced IL-6 gene expression. Furthermore, IL-17, IL-1beta, and TNF-alpha 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-1beta-, or TNF-alpha-induced IL-6 secretion, indicating the role of MAPKs in the induction of IL-6. The combination of either IL-17 plus IL-1beta or IL-17 plus TNF-alpha enhanced IL-6 secretion and IL-6 mRNA expression; in particular, the effects of IL-17 plus TNF-alpha were much stronger than those induced by IL-17 plus IL-1beta. TNF-alpha-induced IL-6 mRNA degraded rapidly at any concentrations, and the combination of IL-17 and TNF-alpha markedly enhanced IL-6 mRNA stability. This indicates that the effects of IL-17 plus TNF-alpha 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.
Shimada
Mitsue
M
Department of Internal Medicine, Shiga University of Medical Science, Seta Tukinowa, Otsu, Japan.
Andoh
Akira
A
Hata
Kazunori
K
Tasaki
Kazuhito
K
Araki
Yoshio
Y
Fujiyama
Yoshihide
Y
Bamba
Tadao
T
D002478:Cells, Cultured; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020871:RNA Stability / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007375:Interleukin-1; D020381:Interleukin-17; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors