Abstract

1,2 -dihydroxyvitamin D3 (1,25-D3) modulates lymphocyte and macrophage functions in vitro. These effects are exerted through production of 1,25-D3 by antigen-presenting monocytes/macrophages (MØ) and binding to vitamin D receptors expressed in MØ and in activated, but not in resting T-lymphocytes. 1,25-D3 inhibits production of MØ-derived cytokines such as interleukin-1a, interleukin-6, and tumor necrosis factor a at the post-transcriptional level, most likely by reducing the half-life of specific mRNAs. The proliferation of T-cells and their release of cytokines such as IL-2 and interferon g are also suppressed by 1,25-D3, partly as a result of the reduced production of T-cell-activating cytokines (interleukin-la, tumor necrosis factor a), but also because of a direct effect on the T-cells. Although 1,25-D3 has no apparent effect on B-lymphocytes, the T-cell suppression indirectly inhibits antibody production by B-cells. The CD45R0+ subset of T-helper cells is relatively more sensitive than the CD45RA+ subset to the inhibitory effects of 1,25-D3. The CD45R0+ subset plays a key role in immune activation and in the pathogenesis of many autoimmune diseases. 1,25-D3 acts as an important local regulator of T-cell functions and thus modulates several immunological effector functions. The actions of 1,25-D3 are distinct from those of commonly used immunosuppressants, and vitamin D3 analogs are therefore potentially useful as alternatives to conventional immunosuppressive therapies.