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J Am Soc Nephrol 13:621-629, 2002
© 2002 American Society of Nephrology

Synthesis of 1,25-Dihydroxyvitamin D3 by Human Endothelial Cells Is Regulated by Inflammatory Cytokines: A Novel Autocrine Determinant of Vascular Cell Adhesion

Daniel Zehnder*, Rosemary Bland*, Ravinder S. Chana*, David C. Wheeler{dagger}, Alexander J. Howie*, Mary C. Williams*, Paul M. Stewart* and Martin Hewison*

*Division of Medical Sciences, The University of Birmingham, Queen Elizabeth Hospital, Birmingham; and {dagger}Centre for Nephrology, Royal Free and University College Medical School, United Kingdom.

Correspondence to Dr. M. Hewison, Division of Medical Sciences, University of Birmingham, Birmingham B15 2TH, UK. Phone: 44-121-414-3776; Fax: 44-121-414-7610; E-mail: M.Hewison{at}bham.ac.uk

ABSTRACT. In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has potent nonclassical effects. In particular, local production of 1,25D3 catalyzed by the enzyme 1{alpha}-hydroxylase (1{alpha}-OHase) may act as an autocrine/paracrine immunomodulatory mechanism. To investigate the significance of this in vascular tissue the expression and function of 1{alpha}-OHase in human endothelial cells was characterized. Immunohistochemical and in situ hybridization analyses show, for the first time, the presence of 1{alpha}-OHase mRNA and protein in endothelial cells from human renal arteries as well as postcapillary venules from lymphoid tissue. Reverse transcription–PCR and Western blot analyses confirmed the presence of 1{alpha}-OHase in primary cultures of human umbilical vein endothelial cells (HUVEC). Enzyme activity in HUVEC (318 ± 56 fmoles 1,25(OH)2D3/hr/mg protein) increased after treatment with tumor necrosis factor–{alpha} (1054 ± 166, P < 0.01), lipopolysaccharide (1381 ± 88, P < 0.01), or forskolin (554 ± 56, P < 0.05). Functional studies showed that exogenously added 1,25(OH)2D3 or its precursor, 25-hydroxyvitamin D3 (25(OH)D3), significantly decreased HUVEC proliferation after 72 h of treatment (33% and 11%, respectively). In addition, after 24 h treatment, both 1,25(OH)2D3 and 25(OH)D3 increased the adhesion of monocytic U937 cells to HUVEC (159% and 153%, respectively). These data indicate that human endothelia are able to produce active vitamin D. The rapid induction of endothelial 1{alpha}-OHase activity by inflammatory cytokines suggests a novel autocrine/paracrine role for the enzyme, possibly as a modulator of endothelial cell adhesion.




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