NDT Advance Access originally published online on February 2, 2006
Nephrology Dialysis Transplantation 2006 21(4):889-897; doi:10.1093/ndt/gfi254
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Vitamin D decreases NF
B activity by increasing IB
levels
1 Department of Clinical Biochemistry and 2 Department of Nephrology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University, PO Box 151, Beer-Sheva, 84101, Israel
Correspondence and offprint requests to: Amos Douvdevani, PhD, Nephrology Laboratory, Soroka University Medical Center, PO Box 151, Beer-Sheva 84101, Israel. Email: amosd{at}bgu.ac.il
Background. In a previous study we demonstrated the inhibitory effect of 1,25-dihydroxyvitamin D (1,25(OH)2D3) and its less calcaemic analog 1,24(OH)2D2 on the production of tumour necrosis factor alpha (TNF
) by human peritoneal macrophages. The aim of the present study is to examine whether this vitamin D inhibition of TNF is mediated by its major transcription factor, nuclear factor-
B (NFB).
Methods. Murine macrophage cells (P388D1) were incubated with 10–7 M 1,25(OH)2D3 or 1,24(OH)2D2 and then stimulated with lipopolysaccharide. NFB activity was assayed using a reporter gene and by electrophoretic mobility shift assay (EMSA). In addition, we evaluated mRNA and protein levels of NFB-p65 and of IB, a potent NFB inhibitor, and phosphorylated IB.
Results. Both 1,25(OH)2D3 and 1,24(OH)2D2 induced a 60% reduction of TNF secretion. By using a reporter gene and EMSA we found that vitamin D markedly reduced NFB activity. 1,25(OH)2D3 or 1,24(OH)2D2 decreased NFB-p65 levels in the nucleus and increased NFB-p65 levels in the cytosol; no changes were observed in the total levels of NFB-p65 protein and mRNA. Concurrently, vitamin D induced a significant increase in mRNA and protein levels of IB (
6.5- and 4.5-fold, respectively). Elevated levels of IB can be explained by the vitamin D-induced prolongation of IB-mRNA half-life from 110 to 190 min and by the decrease in IB phosphorylation.
Conclusions. Vitamin D up-regulates IB levels by increasing mRNA stability and decreasing IB phosphorylation. The increase in IB levels reduces nuclear translocation of NFB and thereby downgrades its activity. Since NFB is a major transcription factor of inflammatory mediators, these findings suggest that the less-calcaemic analog, 1,24(OH)2D2 may be effective as an anti-inflammatory therapeutic agent.
Keywords: IB; macrophages; NFB; tumour necrosis factor alpha; vitamin D
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Talmor, E. Golan, S. Benchetrit, J. Bernheim, O. Klein, J. Green, and G. Rashid Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1059 - F1064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Wu-Wong, M. Nakane, J. Ma, X. Ruan, and P. E. Kroeger Elevated phosphorus modulates vitamin D receptor-mediated gene expression in human vascular smooth muscle cells Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1592 - F1604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chen, G. P. Sims, X. X. Chen, Y. Y. Gu, S. Chen, and P. E. Lipsky Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation J. Immunol., August 1, 2007; 179(3): 1634 - 1647. [Abstract] [Full Text] [PDF]
|
|