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

Abstract

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 effective mechanism for regulating NO production in macrophages through substrate competition. Here, we examined whether IL-13 up-regulates arginase and thus reduces NO production from LPS-activated macrophages. The signaling molecules involved in IL-13-induced arginase activation were also determined. Results showed that IL-13 increased arginase activity through de novo synthesis of the arginase I mRNA and protein. The activation of arginase was preceded by a transient increase in intracellular cAMP, tyrosine kinase phosphorylation, and p38 mitogen-activated protein kinase (MAPK) activation. Exogenous cAMP also increased arginase activity and enhanced the effect of IL-13 on arginase induction. The induction of arginase was abolished by a protein kinase A (PKA) inhibitor, KT5720, and was down-regulated by tyrosine kinase inhibitors and a p38 MAPK inhibitor, SB203580. However, inhibition of p38 MAPK had no effect on either the IL-13-increased intracellular cAMP or the exogenous cAMP-induced arginase activation, suggesting that p38 MAPK signaling is parallel to the cAMP/PKA pathway. Furthermore, the induction of arginase was insensitive to the protein kinase C and p44/p42 MAPK kinase inhibitors. Finally, IL-13 significantly inhibited NO production from LPS-activated 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, tyrosine kinase, and p38 MAPK signalings and underline the importance of arginase in the immunosuppressive activity of IL-13 in activated macrophages.

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

“…Consistent with our findings for H. pylori stimulation, upregulation of arginase II has been reported for RAW 264.7 cells activated by LPS (33) or cAMP (34) and in peritoneal macrophages stimulated by LPS (35). Arginase I expression was not increased in macrophages stimulated by H. pylori, even though this gene has been shown to be induced in macrophages by a cAMP-related pathway (34) involving activation of PKA (36). The signal transduction mechanisms leading to arginase II expression are less well understood.…”

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A2B receptor

“…In addition, when both enzymes are induced together, peroxynitrites, generated by NO synthase 2 under conditions of limiting L-arginine, cause activated T lymphocytes to undergo apoptosis [47]. Interestingly, arginase I induction in macrophages seems to be mediated by the cAMP pathway [48]. According to these data, we could assume that NECA induces, through the cAMP pathway, the differentiation of suppressive DC, since arginase and NO synthase activities are both detected in LPS/ NECA-treated BMDC.…”

Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness

“…3). Although the in vitro kinetics of L-arginine catabolism by iNOS and arginase I appear to normally favor NO production, increased activity of arginase I in intact cells (macrophages, epithelial cells, and at sites of wound healing) can significantly limit the availability of L-arginine for NO synthesis (2,7,18,49,50). Thus, similar to observations made in the Th2-dominated granuloma models induced by S. mansoni egg deposition in the liver (2) and in vitro studies on isolated macrophages (7, 51, 52), IL-13 selectively modulates arginase I FIGURE 7. shRNA, AHP2, induces loss of arginase I but not arginase II function in the lung and inhibits IL-13-induced AHR.…”