title: Regulatory Effect of 25-hydroxyvitamin D3 on Nitric Oxide Production in Activated Microglia.
abstract: Microglia are activated by inflammatory and pathophysiological stimuli in neurodegenerative diseases, and activated microglia induce neuronal damage by releasing cytotoxic factors like nitric oxide (NO). Activated microglia synthesize a significant amount of vitamin D3 in the rat brain, and vitamin D3 has an inhibitory effect on activated microglia. To investigate the possible role of vitamin D3 as a negative regulator of activated microglia, we examined the effect of 25-hydroxyvitamin D3 on NO production of lipopolysaccharide (LPS)-stimulated microglia. Treatment with LPS increased the production of NO in primary cultured and BV2 microglial cells. Treatment with 25-hydroxyvitamin D3 inhibited the generation of NO in LPS-activated primary microglia and BV2 cells. In addition to NO production, expression of 1-α-hydroxylase and the vitamin D receptor (VDR) was also upregulated in LPS-stimulated primary and BV2 microglia. When BV2 cells were transfected with 1-α-hydroxylase siRNA or VDR siRNA, the inhibitory effect of 25-hydroxyvitamin D3 on activated BV2 cells was suppressed. 25-Hydroxyvitamin D3 also inhibited the increased phosphorylation of p38 seen in LPS-activated BV2 cells, and this inhibition was blocked by VDR siRNA. The present study shows that 25-hydroxyvitamin D3 inhibits NO production in LPS-activated microglia through the mediation of LPS-induced 1-α-hydroxylase. This study also shows that the inhibitory effect of 25-hydroxyvitamin D3 on NO production might be exerted by inhibiting LPS-induced phosphorylation of p38 through the mediation of VDR signaling. These results suggest that vitamin D3 might have an important role in the negative regulation of microglial activation.
authors.affiliation: Korea Food Research Institute, Seongnam 463-746, Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Natural Medicine Resources, Semyung University, Jecheon 390-711, Korea.
authors.forename: Pyeongjae
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Physiology, Biomedical Science Institute and Medical Research Center for Reactive Oxygen Species, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, Biomedical Science Institute and Medical Research Center for Reactive Oxygen Species, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
keywords: 1-α-Hydroxylase; 25-Hydroxyvitamin D3; Microglia activation; Vitamin D receptor