Roles of STATs and Src kinases in growth control by IL17

Vanderbilt University, Nashville TN

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Abstract

Interleukin 17 (IL-17) is a CD4+ activated memory T cell derived cytokine. It is a glycosylated homodimeric peptide of 20-30, kDa and it shares 72% and it shares 72% homology with the ORF of the Herpesvirus siamiri 13 gene. Its receptor is a Type 1 Transmembrane non-tyrosine kinase receptor of 120 kDa. The interaction between IL-17 and its receptor is described with a binding affinity constant (Kd) of between 2 x 10-7 and 1.6 x 10-9M. The receptor is ubiquitously expressed in many tissues and cells including NK cells, testis, PBMC, 3T3 fibroblast, H7 mast cells, BB4 muscle cells pre-B cells, IEC6 intestinal cells and THP-1 monocytic progenitor cells. IL-17 has diverse biologic functions. It regulates T cell communication with the hematopoietic system; stimulates maturation of CD34+ progenitors towards neutrophils; stimulates the synthesis of colony stimulator factors (GM-CSF and G-SF); stimulates the synthesis of several cytokines including IL-1, IL-6, IL-8 and TNF; induces myeloid and erythroid progenitor cell proliferation; and regulates immune response via NFkappaB activation. In effect, IL-17 fine-tunes all the phases of hematopoiesis. Because of its important biologic function, IL-17 is under consideration as a cytokine which may play an important role for the clinical management of acute myeloid leukemia, myeloid dysplastic Lymphoma cell growth. In site of its significance, the mechanism by which IL-17 regulates cell growth remains unknown. For example, it is important to identify the key signaling mechanism which transduces major signal from this cytokine to the nucleus leading to nuclear activation and regulation of cell cycle events, which ultimately leads to either immune/inflammatory response or cell proliferation/differentiation. In this study, the main objective is to determine whether specific members of the STAT proteins and Src kinases mediate specific biologic effects of IL-17. The objective can be accomplished using diverse techniques including immunoblot, immunoprecipitation, kinase assays, Cytokine ELISA, DNA Micro Array, RTPCR and Flow Cytometry.