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-hydroxy-vitamin D (25OHD)-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-gamma (IFN gamma) and inhibition by the antiinflammatory glucocorticoid dexamethasone. The data presented here suggest that IFN gamma 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 (IFN gamma)-calcium-modulated eicosanoid metabolism in the regulated synthesis of 1,25-(OH)2D by PAM in sarcoidosis.
Adams
J S
JS
Orthopedic Hospital/University of Southern California Endocrine Research Laboratory, Los Angeles.
Gacad
M A
MA
Diz
M M
MM
Nadler
J L
JL
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004100:Dihydroxycholecalciferols / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D013189:SRS-A / Q000378:metabolism; D012507:Sarcoidosis / Q000378:metabolism*
D001095:Arachidonic Acids; D004100:Dihydroxycholecalciferols; D013189:SRS-A; D016718:Arachidonic Acid; D000001:Calcimycin; D003907:Dexamethasone; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase