INTERLEUKIN 4 (IL-4)

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Interleukin-4 (IL-4) is a multifunctional type I cytokine. Among its most important functions are determining the production of certain immunoglobulin classes, particularly IgE through the regulation of immunoglobulin class switching, and the determination of the differentiation of na?ve CD4+ T cells into TH2 cells. The work covered under this project has been concerned with key biologic functions of IL-4, the means through which IL-4 producing cells appear, and the molecular basis through which IL-4 signaling is accomplished. The IL-4 receptor (R) is a heterodimer consisting of the IL-4 Ra chain and the gc chain. Distinct domains of the receptor largely control IL-4 mediated growth and gene activation. Growth depends upon an IL-4Ra domain centering on Y497; phosphorylated Y497 acts as a docking site for a series of PTB-domain-containing proteins including IRS-1, IRS-2, Shc, and FRIP, a newly identified IL-4 receptor interacting protein. IRS-1, IRS-2 and Shc mediate their function by acting as adapter molecules that recruit pathways leading to growth and resistance to apoptosis. FRIP is a PTB-domain containing protein that appears to inhibit the RAS pathway through it capacity to bind to RAS-GAP and to recruit it to the vicinity of activated RAS. FRIP has recently been shown to be phosphorylated in response to IL-2 , IL-3 and insulin. It is also phosphorylated in response to T cell receptor engagement, although it is not established whether this is direct or indirect. FRIP is hyperphosphorylated in anergic AE7 cells and, in its ability to block the RAS pathway, may play a role in induction or maintenance of the anergic state. IL-4-mediated gene activation and differentiation, such as immunoglobulin class switching and development of na?ve T cells into TH2 cells depend upon the activation of Stat6; such activation is controlled by a more distal portion of the IL-4 Ra chain containing three tyrosines, each one of which, when phosphorylated, appears to be a Stat-6 binding site. These Stat6 sites can be moved to another part of the receptor where they continue to mediate their function of inducing IL-4-specific gene activation. Recent studies indicate that the level of expression of IL-4Ra chain is controlled by a process of phosphorylation/ dephosphorylation. Indeed, mice lacking the phosphatase SHP-1 are defective in IL-4 Ra expression, presumably because of tonic phosphorylation of key tyrosines in the receptor cytosolic domain. Development of naive T cells into IL-4-producing cells is dependent upon IL-4 itself. IL-4Ra chain knockout mice display a major impairment in the development of TH2-type immune responses in response to infection with Nippostrongylus brasiliensis. There does appear to be a potential pathway of development of TH2 cells independent of IL-4 (or IL-13) and of Stat6. It is revealed by the study of BCL6 knockout mice, which develop a severe cardiac and lung inflammatory disease characterized by the production of TH2 cytokines. BCL6 is a transcriptional repressor that interacts with genetic elements similar to those recognized by Stat6 and thus potentially inhibits Stat6; in the absence of BCL6 , TH2 differentiation may occur spontaneously. Indeed, mice that are knockouts for both BCL6 and Stat6 or BCL6 and IL-4 continue to develop the TH2-based inflammatory responses although their peripheral T cells continue to require IL-4 in order to develop into TH2 cells. The development of naive TH precursor cells into TH1 and TH2 cells is a highly regulated process, with the acquisition of IL-4 and IFNg-producing activities being independently controlled. Fully differentiated TH1 cells fail to acquire IL-4-producing capacity even when cultured with antigen in the presence of IL- 4. It has now been shown that fully differentiated TH1 cells display a desensitized IL-4R. IL-4 fails to elicit STAT-6 phosphorylation in such cells. Interestingly, these cells also are deficient in IRS-2, as are cells of STAT-6 KO mice that have been stimulated in vitro in with IL-4. Thus, the induction of the major growth regulatory substrate phosphorylated in response to IL-4 is under the control of STAT-6, explaining how the gene activation function of the IL-4 receptor plays a role in controlling growth. These experiments provide a framework in which to understand the mechanisms through which IL-4 determines the biologic characteristics of immune responses and to identify biochemical steps in its function that may be suitable for the development of antagonists of agonists that could aid in the development of drugs for a variety of allergic, autoimmune, infectious and inflammatory diseases.