IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells

The objectives ofthis study were to determine whether rat aortic smooth muscle cells(RASMC) express arginase and to elucidate the possible mechanismsinvolved in the regulation of arginase expression. The results showthat RASMC contain basal arginase I (AI) activity, which issignificantly enhanced by stimulating the cells with either interleukin(IL)-4 or IL-13, but arginase II (AII) expression was not detectedunder any condition studied here. We further investigated the signaltransduction pathways responsible for AI induction. AI mRNA and proteinlevels were enhanced by addition of forskolin (1 µM) and inhibited byH-89 (30 µM), suggesting positive regulation of AI by aprotein kinase A pathway. Genistein (10 µg/ml) and sodiumorthovanadate (Na₃VO₄; 10 µM) were used toinvestigate the role of tyrosine phosphorylation in the control of AIexpression. Genistein inhibited, whereas Na₃VO₄enhanced the induction of AI by IL-4 or IL-13. Along with immunoprecipitation and immunoblot analyses, these data implicate theJAK/STAT6 pathway in AI regulation. Dexamethasone (Dex) and interferon(IFN)- were investigated for their effects on AI induction. Dex (1 µM) and IFN- (100 U/ml) alone had no effect on basal AI expressionin RASMC, but both reduced AI induction by IL-4 and IL-13. Incombination, Dex and IFN- abolished AI induction by IL-4 and IL-13.Finally, both IL-4 and IL-13 significantly increased RASMC DNAsynthesis as monitored by [³H]thymidine incorporation,demonstrating that upregulation of AI is correlated with an increase incell proliferation. Blockade of AI induction by IFN-, H-89, orgenistein also blocked the increase in cell proliferation. Theseobservations are consistent with the possibility that upregulation ofAI might play an important role in the pathophysiology of vasculardisorders characterized by excessive smooth muscle growth.