1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, calcitriol] has been shown to modulate the immune function of peripheral monocytes and peritoneal macrophages. However, its effect on alveolar macrophage (AM) cytokine secretion has not been reported. We therefore investigated the influence of calcitriol on tumor necrosis factor (TNF-α) production by murine AMs and attempted to elucidate changes in the signal transduction system involved in such effects. Calcitriol significantly enhanced TNF-α secretion by AM stimulated with either lipopolysaccharide (LPS; 10 µg/ml; p < 0.005) or phorbol 12-myristate 13-acetate (PMA; 100ng/ml; p < 0.05) at low doses (between 10-11 and 10-9M). However the protein kinase C (PKC) inhibitor, H7 (10 µM), and the Ca2+/calmodulin inhibitor, W7 (25 µM), reversed such calcitriol effects. Calcitriol increased the total PKC activity of AMs. These findings indicate that calcitriol enhances both LPS- and PMA-stimulated TNF-α secretion through PKC- or Ca2+/calmodulin-dependent p