Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 294, Issue 3, Pages G831-G838Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00535.2007
Keywords
pancreatitis; inflammation; cytokine
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Interleukin (IL)-32 is a recently described proinflammatory cytokine, characterized by the induction of nuclear factor (NF)-kappa B activation. We studied IL-32 alpha 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 alpha protein expression was evaluated by Western blot analyses, and IL-32 alpha mRNA expression was analyzed by Northern blot and real-time PCR analyses. IL-32 alpha mRNA was weakly expressed without a stimulus, and its expression was markedly enhanced by IL-1 beta, IFN-gamma, and TNF-alpha. IL-1 beta, IFN-gamma, and TNF-alpha enhanced intracellular accumulation of IL-32 alpha protein, but IL-32 alpha was not detected in supernatants. Each cytokine dose and time dependently induced IL-32 alpha mRNA expression. An inhibitor of phosphatidylinositol 3-kinase (LY294002) significantly suppressed IL-1 beta-, IFN-gamma-, and TNF-alpha-induced IL-32 alpha 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-1 beta- and TNF-alpha-induced NF-kappa B activation and IL-1 beta-, TNF-alpha-, and IFN-gamma-induced activated protein-1 (AP-1) activation. Blockade of NF-kappa B and AP-1 activation by an adenovirus expressing a stable mutant form of I kappa B alpha and a dominant negative mutant of c-Jun markedly suppressed IL-1 beta-, IFN-gamma-, and/or TNF-alpha- induced IL-32 alpha mRNA expression. Human pancreatic periacinar myofibroblasts expressed IL-32 alpha in response to IL-1 beta, TNF-alpha, and IFN-gamma. IL-32 alpha mRNA expression is dependent on interactions between the phosphatidylinositol 3-kinase/Akt-pathway and the NF-kappa B/AP-1 system.
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