The Type Iii-4 Receptor Complex Selectively Activates The Tyrosine Phosphorylation Of Irs-2

IL-4 and IL-13 participate in the development of allergic inflammation. They elicit many similar functions and share a receptor subunit (IL-4Rα). However, there are reports of differential responses to these cytokines in vitro and in vivo. Therefore, we compared signaling between these cytokines. Human monocytic cell lines or primary mouse macrophages derived from WT or γCKO mice were stimulated with each cytokine; signal transduction was analyzed by western blotting and receptor subunit expression by FACS. IL-4 induced highly efficient tyrosine phosphorylation of IRS-2 in U937 which bear type I IL-4 receptors (γC-positive cells), but not in THP-1 which lack γC. IL-13 did not activate this pathway strongly in either cell type. STAT6 was phosphorylated to maximal levels in both cell types. Enforced γC expression in THP-1 restored phosphorylation of IRS-2 after IL-4 stimulation. IL-4 treatment of primary mouse bone marrow macrophages (BMM) stimulated efficient tyrosine phosphorylation of IRS-2 while BMM from γCKO mice showed minimal tyrosine phosphorylation (30% of wildtype, P < 0.05, n = 4); STAT6 was phosphorylated in both. mRNA for arginase I was highly induced in wildtype BMM after 6 hours of IL-4 treatment (8800×); this was reduced in knockout BMM (1000×). IL-13 induced expression of arginase I mRNA less effectively (500×) at this time point. IL-4 signaling through type I IL-4 receptors selectively induces efficient tyrosine phosphorylation of IRS-2. The γC subunit appears to be responsible for this selectivity, which may influence functional outcomes.