Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 17, Pages 11681-11694Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.517581
Keywords
Cyclooxygenase (COX) Pathway; Lipopolysaccharide (LPS); Macrophages; NF-kappa B (NF-KB); Vitamin D; VDR
Categories
Funding
- Ministry of Science and Technology of China [2012CB945100, 2011CB503906, 2011ZX09307-302-01, 2012BAK01B00]
- National Natural Science Foundation of China [81030004, 31200860]
- Natural Science Foundation of China-Canadian Institutes of Health Research [NSFC81161120538, CIHR-CCI117951]
- Knowledge Innovation Program of the Chinese Academy of Sciences [KSCX2-EW-R-09]
- Clinic Research Center at Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences [CRC2010007]
- Shanghai Institutes for Biological Sciences
- Chinese Academy of Sciences [2012KIP514, 2013KIP312, 2010OHTP10]
- Pujiang Talents Program of Shanghai Municipality [11PJ1411100]
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Background: Vitamin D insufficiency has been associated with chronic inflammatory diseases. However, the underlying mechanisms remain unclear. Results: Vitamin D inhibits COX-2-mediated inflammatory response by modulating the Akt/NF-B signaling pathway via direct up-regulation of thioesterase superfamily member 4. Conclusion: Vitamin D plays novel roles in anti-inflammation. Significance: Supplemental vitamin D could protect against chronic inflammatory diseases by targeting THEM4/Akt/NF-B signaling. Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)(2)D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)(2)D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IB in macrophages were markedly suppressed by 1,25(OH)(2)D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)(2)D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-B/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease.
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