Cytokines are important modulators of the immune response that underlies the inflammatory process in atopic forms of asthma. IL-4 and IL-13 are important cytokines for the regulation of these asthmatic immune responses. However, the cellular mechanisms that regulate IL4 and IL-13 signaling remain unknown. Recently, a new family of proteins, termed Suppressors of Cytokines Signaling (SOCS) has been identified. We have previously shown that SOCS-1 is a potent inhibitor of JAK-STAT signaling activated by IL-4. SOCS-1 expression is regulated both at the RNA and protein stability level. To identify proteins that bind, and potentially regulate, SOCS-1, we used the yeast two-hybrid system. We have identified the serine-threonine kinase Pim-2 as a binding partner for SOCS-1. Our preliminary studies demonstrate that SOCS-1 can interact with all three Pim kinases in mammalian cells. Co-expression of SOCS-1 with Pim kinases leads to the expression of novel SOCS-1 isoforms to require serine-threonine kinase activity. Pim kinases can directly phosphorylate SOCS-1 protein. Finally, expression of Pim-2 increases the inhibition of IL-4 signaling by SOCS-1. These data lead to a model by which the expression of Pim kinases alters SOCS-1 function through a phosphorylation event that stabilizes the SOCS-1 protein. Our grant proposes experiments to test this model and determine the role Pim kinases play in regulating IL-4 signaling in vivo. In addition, we propose to study the role of Pim kinases in a murine model of asthma.
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