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

The objectives of this study were to determine whether rat aortic smooth mu scle cells (RASMC) express arginase and to elucidate the possible mechanism s involved in the regulation of arginase expression. The results show that RASMC contain basal arginase I (AI) activity, which is significantly enhanc ed by stimulating the cells with either interleukin (IL)-4 or IL-13, but ar ginase II (AII) expression was not detected under any condition studied her e. We further investigated the signal transduction pathways responsible for AI induction. AI mRNA and protein levels were enhanced by addition of fors kolin (1 mu M) and inhibited by H-89 (30 mu M), suggesting positive regulat ion of AI by a protein kinase A pathway. Genistein (10 mu g/ml) and sodium orthovanadate (Na3VO4; 10 mu M) were used to investigate the role of tyrosi ne phosphorylation in the control of AI expression. Genistein inhibited, wh ereas Na3VO4 enhanced the induction of AI by IL-4 or IL-13. Along with immu noprecipitation and immunoblot analyses, these data implicate the JAK/STAT6 pathway in AI regulation. Dexamethasone (Dex) and interferon (IFN)-gamma w ere investigated for their effects on AI induction. Dex (1 mu M) and IFN-ga mma (100 U/ml) alone had no effect on basal AI expression in RASMC, but bot h reduced AI induction by IL-4 and IL-13. In combination, Dex and IFN-gamma abolished AI induction by IL-4 and IL-13. Finally, both IL-4 and IL-13 sig nificantly increased RASMC DNA synthesis as monitored by [H-3]thymidine inc orporation, demonstrating that upregulation of AI is correlated with an inc rease in cell proliferation. Blockade of AI induction by IFN-gamma, H-89, o r genistein also blocked the increase in cell proliferation. These observat ions are consistent with the possibility that upregulation of AI might play an important role in the pathophysiology of vascular disorders characteriz ed by excessive smooth muscle growth.