IRS-2 phosphorylation and association with p85 and Grb2 after engagement of type I IL-4 receptor (IL-4R). (38.2)

Abstract

Abstract We previously showed that IL-4 elicited stronger tyrosine phosphorylation of insulin receptor substrate (IRS)-2 than IL-13. This IRS-2 phosphorylation difference was observed even at high concentrations of IL-13 and was due to the exclusive ability of IL-4 to bind to type I IL-4 Rs (IL-4Rα + γC). Furthermore, IL-4 but not IL-13, significantly augmented expression of a subset of alternatively-activated macrophage (AAM) genes, arginase I, found in inflammatory zone (FIZZ)1, and Ym1 in WT bone marrow-derived macrophages (BMM). In this study, we further analyzed signaling differences between IL-4 and IL-13 downstream of the IRS-2 pathway. IL-4 stimulation resulted in enhanced association of the p85 subunit of PI-3' kinase with IRS-2 as compared to IL-13, while only IL-4 induced the association of Grb2 with IRS-2 in WT BMM. Since IRS-2 activation leads to PI-3' K activation, we investigated the effect of wortmannin on induction of the AAM genes. IL-4-induced expression of FIZZ1 was suppressed by wortmannin to the levels induced by IL-13. Arginase I and Ym1 expression was unaffected by wortmannin. These data suggest that the type I IL-4R can direct site-specific phosphorylation of IRS-2, resulting in enhanced recruitment of adaptor molecules and augmented expression of a subset of AAM genes. In addition, they suggest these genes are differentially affected by the IRS-2/PI-3' K pathway. (PHS AI38985)