title: Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4.
abstract: 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)2D 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)2D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IκBα in macrophages were markedly suppressed by 1,25(OH)2D 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)2D 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-κB/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease.
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou 571199, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yuhu
authors.initials: Y
authors.lastname: He
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Caojian
authors.initials: C
authors.lastname: Zuo
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Hong Kong SAR, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Hong Kong SAR, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China; Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Junwen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China. Electronic address: yuying@sibs.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D001483:Base Sequence; D002117:Calcitriol / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011453:Prostaglandins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013869:Thiolester Hydrolases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D011453:Prostaglandins; D002351:Carrageenan; D051546:Cyclooxygenase 2; D013869:Thiolester Hydrolases; D002117:Calcitriol
keywords: Cyclooxygenase (COX) Pathway; Lipopolysaccharide (LPS); Macrophages; NF-kappa B (NF-KB); VDR; Vitamin D