Studies are proposed to analyze the mechanisms through which IL- 4Ralpha chain expression in regulated, both at the basal levels and in its induction during immune responses. In particular, to examine the role of protein tyrosine phosphatases (PTPases) in determining the level of IL-4Ralpha chain expression in basal and in the IL-4-induction state. To study the role PTPases in regulating IL-4Ralpha chain expression, experiements are proposed to: 1. Study the role of SHP-1 in regulating expression of IL-4Ralpha chain. a. Examine the expression of IL-4Ralpha chain and other type I cytokine receptors ofmotheaten mice. b. Examine whether SHP-1 directly regulates IL-4Ralpha chain expression. 2. Study the role of PTPases in regulating induced expression of IL-4Ralpha chain. a. Establish whether, in the absence of PTPase activity, induced IL- 4Ralpha chains become degraded. b. To determine whether hyperphosphorylation of the IL-4Ralpha chain is a prerequisite for IL-4Ralpha chain degradation; if it is, to determine what sites on the receptor are critically important. c. Determine what segments of IL-4Ralpha chain is/are required for the interaction with SHP-1 and other PTPases and effect of these interaction on IL-4Ralpha chain expression. 3. To study the cellular sites and mechanisms of IL-4Ralpha chain degradation. IL-4 play the key role in mediating any biological functions, including affecting the outcomes of many infectious and autoimmune diseases. The proposed study will provide an insight into a novel mechanism regulating IL-4 receptor signaling.
| Huang, Zan; Coleman, John M; Su, Yan et al. (2005) SHP-1 regulates STAT6 phosphorylation and IL-4-mediated function in a cell type-specific manner. Cytokine 29:118-24 |
| Zhang, Y; Apilado, R; Coleman, J et al. (2001) Interferon gamma stabilizes the T helper cell type 1 phenotype. J Exp Med 194:165-72 |
