Vitamin D Inhibits COX-2 Expression and Inflammatory Response by Targeting Thioesterase Superfamily Member 4

Qingsong Wang, Yuhu He, Yujun Shen, Qianqian Zhang, Di Chen, Caojian Zuo, Jing Qin, Hui Wang, Junwen Wang, Ying Yu
2014 Journal of Biological Chemistry  
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.
more » ... uate 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. 3 The abbreviations used are: 1,25(OH) 2 D, 1,25-dihydroxy-vitamin D; VDR, vitamin D receptor; VDRE, vitamin D-responsive element; COX, cyclooxygenase; PG, prostaglandin; THEM4, thioesterase superfamily member 4; NSAID, nonsteroidal anti-inflammatory drug; KD, knockdown; FFA, free fatty acid.
doi:10.1074/jbc.m113.517581 pmid:24619416 pmcid:PMC4002078 fatcat:cry22krggbhjzhtyv5wjuys5xu