A ROLE FOR ENDOGENOUS ARACHIDONATE METABOLITES IN THE REGULATED EXPRESSION OF THE 25-HYDROXYVITAMIN-D-1-HYDROXYLATION REACTION IN CULTURED ALVEOLAR MACROPHAGES FROM PATIENTS WITH SARCOIDOSIS

In the human granulomatous disease sarcoidosis hypercalcemia and/or hypercalciuria result from the endogenous overproduction of 1, 25-dihydroxyvitamin D [1, 25-(OH)2D] by the disease-activated macrophage. Unlike the renal 25-hydroxyvitamin D (250HD)-1-hydroxylase, normally the sole synthetic source of the hormone in man, the 25OHD3-1-hydroxylation reaction in cultured pulmonary alveolar macrophages (PAM) from patients with sarcoidosis is subject to stimulation by the immune cytokine interferon-γ (IFNγ) and inhibition by the antiinflammatory glucocorticoid dexamethasone. The data presented here suggest that IFNγ and calcium ionophore A23187 promote enhanced expression of the sarcoid PAM 25OHD3-1-hydroxylation reaction by increasing endogenous arachidonic acid metabolism through the 5-lipoxygenase pathway. Dexamethasone, an inhibitor of the cellular phospholipase-A2-arachidonic acid-generating system, and BW755C, a lipoxygenase pathway inhibitor, inhibited PAM 1, 25-(OH)2D3 synthesis by 64% and 54%, respectively. Conversely, leukotriene C4, a distal metabolite in the arachidonic acid 5-lipoxygenase pathway, increased the hydroxylation reaction by 234% and restored dexamethasone-inhibited PAM 1, 25-(OH)2D3 synthetic activity. The results of this study provide presumptive evidence for an important role of agonist (IFNγ)-calcium-modulated eicosanoid metabolism in the regulated synthesis of 1, 25-(OH)2D by PAM in sarcoidosis. © 1990 by The Endocrine Society.