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.
| Melillo, Jessica A; Song, Li; Bhagat, Govind et al. (2010) Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J Immunol 184:2638-45 |
| Schindler, Christian; Plumlee, Courtney (2008) Inteferons pen the JAK-STAT pathway. Semin Cell Dev Biol 19:311-8 |
| Rastogi, Deepa; Wang, Chaodong; Mao, Xia et al. (2007) Antigen-specific immune responses to influenza vaccine in utero. J Clin Invest 117:1637-46 |
| Harbers, Stephanie O; Crocker, Andrea; Catalano, Geoffrey et al. (2007) Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance. J Clin Invest 117:1361-9 |
| Desai, Dharmesh D; Harbers, Stephanie O; Flores, Marcella et al. (2007) Fc gamma receptor IIB on dendritic cells enforces peripheral tolerance by inhibiting effector T cell responses. J Immunol 178:6217-26 |
| Rastogi, D; Wang, C; Lendor, C et al. (2006) T-helper type 2 polarization among asthmatics during and following pregnancy. Clin Exp Allergy 36:892-8 |
| Kashiwada, Masaki; Cattoretti, Giorgio; McKeag, Lisa et al. (2006) Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+ T cell development. J Immunol 176:3958-65 |
| Kisseleva, Tatiana; Song, Li; Vorontchikhina, Marina et al. (2006) NF-kappaB regulation of endothelial cell function during LPS-induced toxemia and cancer. J Clin Invest 116:2955-63 |
| Fanzo, Jessica C; Yang, Wen; Jang, So Young et al. (2006) Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest 116:703-14 |
| Vuong, Bao Q; Arenzana, Teresita L; Showalter, Brian M et al. (2004) SOCS-1 localizes to the microtubule organizing complex-associated 20S proteasome. Mol Cell Biol 24:9092-101 |
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