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

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. © 2016 the authors