title: Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages.
abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive cortisone to the active cortisol. 11β-HSD1 may be involved in the resolution of inflammation. In the present study, we investigate the anti-inflammatory effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a selective 11β-HSD1 inhibitor, in lipopolysaccharide (LPS)-activated C57BL/6J mice and macrophages. LPS increased 11β-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFκB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344. Taken together, KR-66344 protects against LPS-induced animal death and spleen injury by inhibition of inflammation via induction of HO-1 and inhibition of 11β-HSD1 activity. Thus, we concluded that the selective 11β-HSD1 inhibitor may provide a novel strategy in the prevention/treatment of inflammatory disorders in patients.
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Sung Bum
authors: SB
authors: Park
authors: Department of Human and Environmental Toxicology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors: Ji Seon
authors: JS
authors: Park
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Won Hoon
authors: WH
authors: Jung
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Hee Youn
authors: HY
authors: Kim
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Hyun Jung
authors: HJ
authors: Kwak
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Jin Hee
authors: JH
authors: Ahn
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Kyoung-Jin
authors: KJ
authors: Choi
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Yoon-Ju
authors: YJ
authors: Na
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Sunhwa
authors: S
authors: Choi
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea.
authors: Sang
authors: S
authors: Dal Rhee
authors: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address: kykim@krict.re.kr.
authors: Ki Young
authors: KY
authors: Kim
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004347:Drug Interactions; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015996:Survival Rate; D013843:Thiazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C558395:2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone; D000893:Anti-Inflammatory Agents; D003499:Cyclic S-Oxides; D008070:Lipopolysaccharides; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D013843:Thiazines; C017803:zinc protoporphyrin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: 11β-Hydroxysteroid dehydrogenase type 1; Anti-inflammatory effect; Heme oxygenase-1; Lipopolysaccharide