It is well established that monocytes and activated lymphocytes express the receptor for 1,25 dihydroxyvitamin D3 (1,25(OH)2D3); and that 1,25(OH)2D3, acting via its receptor can modulate the proliferation of lymphocytes as well as the production of cytokines including Interleukin-1 (IL-1); Interleukin-2 (IL-2); delta- Interferon (delta-IFN) and the granulocyte-macrophage colony stimulating factor (GM-CSF). The cellular requirements, the molecular and the relevance of these phenomena to health or disease remain unclear. We have recently determined that the 1,25(OH)2D3 induced inhibition of IL-2 and lymphocyte proliferation depends largely upon the presence of monocytes; and the exposure of monocytes to 1,25(OH)2D3 causes a pronounced inhibition of the production and releases of IL-1a and IL-1b. Modulation of delta-IFN and GM-CSF production on the other hand appears to be the result of direct actions of 1,25(OH)2D3 on T-cells and is independent of the hormonal influence on their proliferation. More intriguingly, we found that 1,25(OH)2D3 can either stimulate or inhibit production of delta- IFN depending upon the nature of the signal that activates the T- cells. These observations suggest that the overall effect of 1,25(OH)2D3 on immune phenomena must be the sum of its actions on both monocytes and lymphocytes as well as of modifying influences on biochemical events associated with the transduction of signals arising from the lymphocyte cell membrane. Moreover, they raise the possibility that the role of 1,25(OH)2D3 in immunoregulation might be both that of a stimulator and that of a suppressor. To investigate this possibility and in order to dissect the cellular requirements and the mechanism(s) underlying the immunoregulatory properties of 1,25(OH)2D3, we propose to study its effects on the expression of the genes encoding for IL-2; alpha and delta-IFN; and GM-CSF using normal human and mouse lymphocytes as well as established antigen-specific T-cell lines that will be activated in the presence or absence of monocytes and via antigen- specific or non-specific pathways. In addition we shall to elucidate the mechanism of the phenomenon whereby the effect of 1,25(OH)2D3 on the expression of lymphokines is altered depending upon the mode of activation of the T-cells by searching for potential influences of 1,25(OH)2D3 on the following biochemical events involved in signal transduction: Phosphatidyl inositol pathway, adenylate cyclase and intracellular levels of CA+2. Finally, we propose to administer pharmacologic doses of 1,25(OH)2D3 to MRL/1 mice, a well characterized model of generalized autoimmunity, and examine the influence of the treatment on cellularity and composition of cells in lymphoid organs, in-vitro production and responsiveness to cytokines, immunoglobulin production as well as histologic features of the arthritic process in the joint of these animals.
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