CALCITRIOL AND ITS SYNTHETIC ANALOG MC-903 INHIBIT THE INTERLEUKIN-2-INDUCED MIGRATION OF HUMAN-LYMPHOCYTES

Sarcoidosis is characterized by the accumulation of activated lymphocy tes in the lungs and other organs and by the spontaneous production of the active form of vitamin D, calcitriol. We hypothesized that calcit riol may modulate the responsiveness of human lymphocytes to the relev ant biologic mediator, interleukin-2 (IL-2). After culture for 48 h wi th phytohemagglutinin, human peripheral blood lymphocytes migrated thr ough nitrocellulose filters, secured in microchemotaxis chambers, in r esponse to IL-2. When calcitriol at 1 nM was included in the cultures, the migratory response to IL-2 was completely abrogated. This inhibit ory effect was seen despite the fact that cultured lymphocytes continu ed to express the IL-2 receptor and other activation markers. A simila r but more rapid effect could be demonstrated by including calcitriol in the lower well during our 3-h chemokinesis assay. Calcitriol blocke d IL-2-induced lymphocyte migration in a dose-dependent fashion. The s ynthetic noncalcemic vitamin D analogue MC 903 was equally effective i n this assay. IL-2-induced migration could also be prevented by the pr otein kinase C inhibitor H-7, but calcitriol appeared to be at least 1 ,000 times more potent. Our studies suggest that calcitriol is a poten t natural immunomodulator with rapid suppressive effects that may be m ediated through protein kinase C. Synthetic analogues such as MC 903 m ay offer exciting therapeutic opportunities.