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

The Journal of Clinical Endocrinology and Metabolism
John S AdamsJ L Nadler

Abstract

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 act...Continue Reading

Citations

Dec 1, 1990·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·J S AdamsT L Clemens
Oct 1, 1996·Australian and New Zealand Journal of Medicine·N J Cook, F R Lake
Feb 1, 1994·Experimental Dermatology·L KeményT Ruzicka
May 13, 1999·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·S J SmithE B Mawer
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Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·L EstebanA Dusso
Nov 14, 2019·Chronic Respiratory Disease·Łukasz GwaderaWojciech Jerzy Piotrowski
Sep 3, 2016·Endocrine Reviews·Peter J TebbenRajiv Kumar
Aug 1, 1991·The Journal of Investigative Dermatology·P MildeE W Rauterberg

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