NDT Advance Access published online on February 2, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfi254
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1 Department of Clinical Biochemistry, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University, PO Box 151, Beer-Sheva, 84101, Israel; Department of Nephrology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University, PO Box 151, Beer-Sheva, 84101, Israel
* To whom correspondence should be addressed. 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 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. NF Results. Both 1,25(OH)2D3 and 1,24(OH)2D2 induced a 60% reduction of TNF Conclusions. Vitamin D up-regulates I
Received March 17, 2005
Accepted October 13, 2005
Original Article
Vitamin D decreases NF
Merav Cohen-Lahav 1,
Shraga Shany 2,
David Tobvin 3,
Cidio Chaimovitz 3,
and
Amos Douvdevani 1 *
B activity by increasing IB
levels
2 Department of Clinical Biochemistry, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University, PO Box 151, Beer-Sheva, 84101, Israel
3 Department of Nephrology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University, PO Box 151, Beer-Sheva, 84101, Israel
Amos Douvdevani, E-mail: amosd{at}bgu.ac.il
Abstract 
) 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).B 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. 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.B 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.B; macrophages; NFB; tumour necrosis factor alpha; vitamin D.
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