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-1, IL-6, TNF and IL-8), colony stimulating factors (GM- CSF and G-CSF) and ICAM in fibroblasts. HIL-17 stimulates U937 leukemia cell proliferation. It is considered to be a vehicle for fine tuning hematopoiesis. Based on its ability to stimulate IL-8 production, hIL-17 is considered to play a role in pro-inflammatory response. Because of its ability to regulate hematopoiesis, it is predicted to emerge as a future clinical tool for the management of acute myeloid leukemia, erythroleukemia, immune disorders (T and B cell malignancies) and bone marrow suppression. In spite of its elaborate biologic functions, information on its mechanisms of action is lacking. Therefore, the question of how this cytokine transduces it signal to the nucleus leading to growth regulation and cytokine production awaits 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 whether Tyk2, STAT4, STAT5 and STAT6 are activated by hIL-17, (2) determination of whether Tyk2, STAT4, STAT5 and STAT6 are activated by hIL-17, (2) determination of whether activation of specific Jak/STAT proteins by hIL-17 correlates with the DNA binding of specific STAT complexes and cytokine gene expression, and (3) determination of whether activation of specific Jak/STAT protein by hIL-17 correlates with the status of cell proliferation/differentiation and cytokine production. By conducting these studies, we will make significant contributions towards the understanding of the mechanisms of action of hIL-17. The outcome would be beneficial to physicians and immunologists for future design of strategies on applications of hIL-17 for the management of diseases of abnormal hematopoiesis and immune system. By employing various techniques including antisense oligonucleotide therapy, Western/Northern blot hybridization, ELISA, immunoprecipitation, kinase assays, PCR and flow cytometry, we can accomplish these aims within three years.

R03AR046384

1999-09-15

2004-08-31