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Inhibition of Interleukin-1 Production by 1,25-Dihydroxyvitamin D₃

Department of Biology and Molecular Biology Institute, San Diego State University San Diego, California 92182
Department of Basic and Department of Clinical Research La Jolla, California 92037
Department of Immunology, Department of Scripps Clinic and Research Foundation La Jolla, California 92037
Department of Medicine, New England Medical Center Hospitals Boston, Massachusettes 02111
Section of Endocrinology and Metabolism, Veterans Administration Medical Center Indianapolis, Indiana 46202

Address requests for reprints to: Dr. Constantine D. Tsoukas, Department of Biology and Molecular Biology Institute, San Diego State University, San Diego, California 92182.

The hormonal form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃], inhibits the proliferation of T lymphocytes and production of growth-promoting factors [including interleukin-2) (IL2) in CTLL2 murine cells. In this study, we investigated the role of monocytes in this hormone-mediated inhibitory effect, by testing the effects of 1,25-(OH)₂D₃ on the ability of the mitogenic lectin phytohemagglutinin (PHA) to induce T cell activation in either a monocyte-dependent or phorbol myristate acetate (PMA)-driven (monocyte-independent) system. The results indicate that proliferation of T cells and production of growth-promoting factors are inhibited by 1,25-(OH)₂D₃ only in the monocyte-dependent system.

Preincubation of monocytes with 1,25-(OH)₂D₃ for various periods of time and subsequent removal of the hormone resulted in inhibition of the PHA-driven proliferation of T cells. Preincubation for 2 h resulted in 20% inhibition, while preincubation for 36 h reduced proliferation to 50% of the control value [no 1,25-(OH)₂D₃ exposure].

These data suggested that monocytes are important participants in l,25-(OH)₂D₃-mediated events. Therefore, we tested the effects of the hormone on the production of IL1, a monocytederived product thought to be involved in the induction of IL2 release and the subsequent development of the T cell proliferative response. 1,25-(OH)₂D₃ inhibited the production of both extracellular and cell-associated immunoreactive IL1 and IL1β. Indomethacin, a prostaglandin synthetase inhibitor, did not alter the inhibitory properties of 1,25-(OH)₂D₃, suggesting that prostaglandins are not responsible for the inhibitory phenomenon.

We conclude that part of the ability of 1,25-(OH)₂D₃ to inhibit T cell proliferation may be due to direct effects on monocytes by down-regulating IL-1 production. However, it is unlikely that the immunoregulatory properties of 1,25-(OH)₂D₃ on T cells are mediated solely through monocytes, and it is possible that the hormone also exerts its influence directly on T cells.

Received August 15, 1988.

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