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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/G831    most recent 00535.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nishida, A. Articles by Fujiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Nishida, A. Articles by Fujiyama, Y.

INFLAMMATION/IMMUNITY/MEDIATORS

Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-32 induction in human pancreatic periacinar myofibroblasts

¹Department of Medicine, Shiga University of Medical Science, Otsu; ²Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto; and ³Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan

Submitted 16 November 2007 ; accepted in final form 30 January 2008

Interleukin (IL)-32 is a recently described proinflammatory cytokine, characterized by the induction of nuclear factor (NF)-B activation. We studied IL-32 expression in human pancreatic periacinar myofibroblasts, which play important roles in the regulation of extracellular matrix metabolism and inflammatory responses in the pancreas. IL-32 protein expression was evaluated by Western blot analyses, and IL-32 mRNA expression was analyzed by Northern blot and real-time PCR analyses. IL-32 mRNA was weakly expressed without a stimulus, and its expression was markedly enhanced by IL-1β, IFN-, and TNF-. IL-1β, IFN-, and TNF- enhanced intracellular accumulation of IL-32 protein, but IL-32 was not detected in supernatants. Each cytokine dose and time dependently induced IL-32 mRNA expression. An inhibitor of phosphatidylinositol 3-kinase (LY294002) significantly suppressed IL-1β-, IFN--, and TNF--induced IL-32 mRNA expression, although MAPK inhibitors had no effect. Akt activation in response to these cytokines was confirmed by Western blot. Furthermore, LY294002 suppressed both IL-1β- and TNF--induced NF-B activation and IL-1β-, TNF--, and IFN--induced activated protein-1 (AP-1) activation. Blockade of NF-B and AP-1 activation by an adenovirus expressing a stable mutant form of IB and a dominant negative mutant of c-Jun markedly suppressed IL-1β-, IFN--, and/or TNF--induced IL-32 mRNA expression. Human pancreatic periacinar myofibroblasts expressed IL-32 in response to IL-1β, TNF-, and IFN-. IL-32 mRNA expression is dependent on interactions between the phosphatidylinositol 3-kinase/Akt-pathway and the NF-B/AP-1 system.

pancreatitis; inflammation; cytokine