Human Interleukin-17 (hIL-17) is novel a cytokine produced by activated T cells. hIL-17 induces T cell proliferation and stimulates production of cytokines (IL-6 and IL-8), colony stimulating factors (GM-CSF and G- CSF) and ICAM in fibroblasts. hIL-17 is considered to be a vehicle for fine tuning hematopoiesis. Based on its ability to regulate hematopoiesis, it is predicted to emerge as a future clinical tool for the management of acute myeloid leukemia, erythroleukemia and immune disorders including T and B malignancies and bone marrow suppression. In spite of its elaborate biologic functions, no information exists on its mechanisms of action. For instance, the question of how this cytokine transduces it signal to the nucleus leading to growth regulation and cytokine production is yet to be addressed. The overall goal of this investigation is to elucidate the mechanisms of action of this novel cytokine. Our immediate specific aims are (1) determination of wh of whether specific components of the Jak/Stat signaling pathway mediate the biologic effects of hIL-17, (2) determination of the possible roles of Ras/MAPK and PKC signaling pathways in the mechanisms of hIL-17, (3) determination of whether Lyn, Fyn, Lck and ZAP-70 play a role in the mechanisms of hIL-17, and (4) elucidate the mechanisms of cytokine gene regulation by hIL-17. By conducting these studies, we anticipate on making significant contributions towards the understanding the mechanisms of action of this novel cytokine. Also, the outcome would assist physicians and immunologists in their future applications of hIL-17 for the management of numerous human diseases which are related to abnormal hematopoiesis. By employing a host of techniques including antisense oligonucleotide therapy, Western/Northern blot hybridization ELISA immunoprecipitation, kinase assays, PCR and flow cytometry, we are confident that these aims could be accomplished within four years.
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