The involvement of tyrosine kinases, cyclic AMP/protein kinase A, and p38 mitogen-activated protein kinase in IL-13-mediated arginase I induction in macrophages: Its implications in IL-13-inhibited nitric oxide production

In macrophages, L-arginine can be used by NO synthase and arginase to form NO and urea, respectively. Therefore, activation of arginase may be an effe ctive mechanism for regulating NO production in macrophages through substra te competition. Here, we examined whether IL-13 up-regulates arginase and t hus reduces NO production from LPS-activated macrophages, The signaling mol ecules involved in IL-13-induced arginase activation were also determined, Results showed that IL-13 increased arginase activity through de novo synth esis of the arginase I mRNA and protein. The activation of arginase was pre ceded by a transient increase in intracellular cAMP, tyrosine kinase phosph orylation, and p38 mitogen-activated protein kinase (MAPK) activation. Exog enous cAMP also increased arginase activity and enhanced the effect of IL-1 3 on arginase induction. The induction of arginase was abolished by a prote in kinase A (PKA) inhibitor, KT5720, and was down-regulated by tyrosine kin ase inhibitors and a p38 MAPK inhibitor, SB203580. However, inhibition of p 38 MAPK had no effect on either the IL-13-increased intracellular cAMP or t he exogenous cAMP-induced arginase activation, suggesting that p38 MAPK sig naling is parallel to the cAMP/PKA pathway. Furthermore, the induction of a rginase was insensitive to the protein kinase C and p44/p42 MAPK kinase inh ibitors, Finally, IL-13 significantly inhibited NO production from LPS-acti vated macrophages, and this effect was reversed by an arginase inhibitor, L -norvaline, Together, these data demonstrate for the first time that IL-13 down-regulates NO production through arginase induction via cAMP/PKA, tyros ine kinase, and p38 MAPK signalings and underline the importance of arginas e in the immunosuppressive activity of IL-13 in activated macrophages.