Influence of vitamin D3 metabolites on the production of interleukins 1,2 and 3.

We investigated the effect of vitamin D3 metabolites on the release of the three interleukins (IL) IL 1, IL 2 and IL 3 by mononuclear cells. Models for the production of these mediators were the release of IL 1 by the murine macrophage cell line P388D1, of IL2 by rat spleen cells, and of IL 3 by the murine WEHI-3 cell line. IL 1 production was significantly increased with 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) at 10(-10)M and above. 1,25(OH)2D3 did not stimulate cell proliferation as assessed with [methyl-3H]thymidine (3H-TdR) incorporation. 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and 25-hydroxyvitamin D3 (25(OH)D3) were about 1000 times less effective than 1,25(OH)2D3. IL 2 production, by cultured rat spleen cells stimulated with Concanavalin A, was decreased by increasing concentrations of 1,25(OH)2D3. The minimal effective dose varied between experiments and ranged from 10(-11) to 10(-8) M. Moreover, proliferation (3H-TdR incorporation) of mouse thymocytes treated with phytohemagglutinin and IL 1 was decreased in a dose-dependent fashion by 1,25(OH)2D3 starting at 10-11) M. This effect might be secondary to a decrease of endogenous IL 2 production. IL 3 release by WEHI-3 cells was significantly increased with 10(-11)-10(-9) M 1,25(OH)2D3, whereas higher concentrations were less effective or decreased IL 3 production. These results show that 1,25(OH)2D3 and, to a lesser extent, 24,25(OH)2D3 and 25(OH)D3 have selective effects on lymphokine production. It is tempting to speculate that the actions of 1,25(OH)2D3 on bone might in part be mediated by lymphokines. Moreover, we suggest that 1,25(OH)2D3 might not be an immunoregulator per se, but makes use of the immune system to exert its influence on one of its classical targets, namely the bone, and possibly on other connective tissues.