STIMULATORY EFFECT OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 ON MOUSE ALVEOLAR MACROPHAGE TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION IN-VITRO - INVOLVEMENT OF PROTEIN-KINASE-C AND CA2-DEPENDENT KINASE( CALMODULIN)

1 alpha,25-Dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3, calcitriol] has been shown to modulate the immune function of peripheral monocytes an d peritoneal macrophages. However, its effect on alveolar macrophage ( AM) cytokine secretion has not been reported. We therefore investigate d the influence of calcitriol on tumor necrosis factor (TNF-alpha) pro duction by murine AMs and attempted to elucidate changes in the signal transduction system involved in such effects. Calcitriol significantl y enhanced TNF-alpha secretion by AM stimulated with either lipopolysa ccharide (LPS; 10 mu g/ml; p < 0.005) or phorbol 12-myristate 13-aceta te (PMA; 100 ng/ml; p < 0.05) at low doses (between 10(-11) and 10(-9) M). However the protein kinase C (PKC) inhibitor, H7 (10 mu M), and t he Ca2+/calmodulin inhibitor, W7 (25 mu M), reversed such calcitriol e ffects. Calcitriol increased the total PKC activity of AMs. These find ings indicate that calcitriol enhances both LPS- and PMA-stimulated TN F-alpha secretion through PKC- or Ca2+/calmodulin-dependent pathways.