Calcitriol and calcium regulate cytokine production and adipocyte-macrophage cross-talk.

OBJECTIVE The objective of this study was to investigate the effects of calcitriol on adipocyte and macrophage cytokine expression as well as release and on adipocyte-macrophage cross-talk in local modulation of inflammation. RESEARCH PROCEDURES AND RESULTS We investigated calcitriol modulation of the expression of macrophage inhibitory factor (MIF) and macrophage surface-specific protein CD14, two key factors in regulating macrophage function and survival, in differentiated human adipocytes. Calcitriol significantly increased MIF and CD14 expression by 59% and 33%, respectively, while calcium-channel antagonism with nifedipine completely reversed these effects, indicating that calcitriol stimulates MIF and CD14 expression via a calcium-dependent mechanism. Similar results were also found in cultured 3T3-L1 adipocytes; in addition, calcitriol also up-regulated macrophage colony-stimulating factor, macrophage inflammatory protein, interleukin-6 (IL-6) as well as monocyte chemoattractant protein-1 expression in 3T3-L1 adipocytes and stimulated tumor necrosis factor as well as IL-6 expression in RAW 264 macrophages. These effects were blocked by either a calcium-channel antagonist (nifedipine) or a mitochondrial uncoupler (dinitrophenol). Moreover, co-culture of 3T3-L1 adipocytes with RAW 264 macrophages significantly increased the expression and production of multiple inflammatory cytokines in response to calcitriol in both cell types. CONCLUSIONS These data demonstrate that calcitriol regulates local inflammation via modulating the interaction between adipocytes and macrophages as well as regulating inflammatory cytokine production in each cell type via calcium-dependent and mitochondrial uncoupling-dependent mechanisms. These data provide further mechanistic explanation for our recent observations that suppression of calcitriol by dietary calcium reduces inflammatory cytokine expression and oxidative stress in adipose tissue.