Interleukin 4 (IL-4) is a potent cytokine produced by T cells and to a lesser extent by tumor-associated natural killer cells, basophils, and mast cells. IL-4 treatment of T cells and macrophages leads to augmentation of their cytotoxic activity. In human B cells, IL-4 is a potent stimulator of Ig class switching from IgM to IgE. The diverse biological responses induced by IL-4 are mediated through a high affinity receptor complex (IL-4R).Although a wealth of information has accumulated regarding IL-4R, the exact mechanisms of IL-4R-mediated signaling pathways in human B cells are not well defined. In an attempt to characterize the IL-4-induced signals in human B cells, we have found that IL-4 treatment induced rapid dephosphorylation of the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase. To identify the protein-tyrosine phosphatase involved in the IL-4-mediated dephosphorylation, we performed Western blot analysis using monoclonal antibodies specific to protein-tyrosine phosphatases. Upon IL-4 treatment, SHP-1 was specifically translocated to the cellular membrane fraction. Furthermore, immunoprecipitation studies revealed that SHP-1 could be specifically coimmunoprecipitated with the IL-4R as well as with phosphatidylinositol 3-kinase (p85). Collectively, our observations suggest that in addition to protein phosphorylation, protein tyrosine dephosphorylation may play a role in the IL-4-induced signaling pathways.
IL-41 is a potent cytokine with pleiotropic effects on many cell types. The biological effects of IL-4 include induction of IgE class switching, induction of proliferation in T and B cells, and up-regulation of CD23 and major histocompatibility complex class II molecules on human B cells (1-4).The IL-4 receptor complex is present on many hematopoietic and non-hematopoietic cell lines (5). Although many members of the cytokine receptor family, including the IL-4 receptor (IL-4R), lack protein kinase consensus domains, ligand binding to these receptors results in tyrosine phosphorylation as well as dephosphorylation and subsequent biological responses (6, 7).Early studies of Morla et al. (8) reveal IL-4-induced tyrosine phosphorylation of proteins of 110 and 170 kDa in a murine mast cell line, IC 2.9. Subsequently, Wang et al. (9) reported IL-4-induced tyrosine phosphorylation of a 170-kDa polypeptide, termed 4PS in murine myeloid cell lines. Keegan et al. (10) reported that 4PS may be antigenically and functionally similar to the insulin receptor substrate-1. Additional evidence of IL-4-induced signal transduction events was demonstrated by the IL-4-induced association of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) with the phosphorylated form of 4PS; however, p85 itself was not phosphorylated (11).Further studies have shown that IL-4 treatment induces the association of IL-4R with the ␥ chain of the IL-2 receptor complex (12) that participates in IL-4-mediated signaling by ␥ chain-associated JAK kinases (13,14). However, experiments by He and Malek (15) provide evidence f...