This project is aimed at exploring the mechanisms by which 1,25 (OH)2D and IL-1 promote helper T lymphocyte proliferation. These issues are particularly germane to understanding the pathogenesis of osteoporosis as 1) both 1,25 (OH)2D and IL-1 are potent bone resorbing agents which target to immune cells, 2) the immune system probably plays an important role in regulating skeletal remodeling, and 3) abnormal production of both agents has been associated with osteoporosis. Our studies will utilize two non-transformed helper T cell lines. As regards the effect of 1,25 (OH)2D on T cell proliferation, we have shown that the steroid is a potent mitogen of the clone under study, and Specific Aim #1 is directed at exploring the cellular mechanisms underlying this proliferative phenomenon. These studies will focus on the capacity of the steroid to induce or increase the expression of growth factors known to enhance T lymphocyte growth (e.g., IL-1, IL-2, BSF-1) and/or increase the number of their respective cell membrane receptors.
Specific Aim #2, on the other hand, focuses on the means by which IL-1 stimulates T cell proliferation. Although Il-1 is known to be a pivotal T cell growth factor, its mitogenic effect generally requires a co-stimulus such as specific antigen or lectin. As it is difficult to distinguish IL-1 mediated effects on lymphocytes from thos of a co-mitogen, the means by which IL-1 promotes T cell replication are unknown. Alternatively, we have developed another T cell line which uniquely responds to IL-1 alone without the necessity of a co-mitogen, placing us in a position to explore the precise effects of this growth factor on lymphocytes. These experiments will focus on the capacity of IL- 1 to effect immediate alterations in cellular protein phosphorylation and will explore the possible involvement of either protein kinase C or tyrosine kinase in the IL-1 mediated effects.
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