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5α‐Reduced glucocorticoids exhibit dissociated anti‐inflammatory and metabolic effects
Author(s) -
Yang C,
Nixon M,
Kenyon CJ,
Livingstone DEW,
Duffin R,
Rossi AG,
Walker BR,
Andrew R
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01465.x
Subject(s) - corticosterone , endocrinology , medicine , in vivo , glucocorticoid , cytokine , inflammation , tumor necrosis factor alpha , glucocorticoid receptor , chemistry , immune system , secretion , biology , immunology , hormone , microbiology and biotechnology
BACKGROUND AND PURPOSE Dissociating anti‐inflammatory efficacy from the metabolic side effects of glucocorticoids is an attractive therapeutic goal. 5α‐Tetrahydro‐corticosterone (5αTHB), produced from corticosterone by 5α‐reductases, activates glucocorticoid receptors. This study compares the effects of 5αTHB on inflammation and metabolism in vitro and in vivo . METHODS Suppression of cytokine release by 5αTHB and corticosterone were studied following LPS activation of mouse bone marrow derived macrophages. In vivo the efficacy of these steroids to dysregulate metabolic homeostasis and modulate immune suppression and the responses to thioglycollate‐induced peritonitis in C57BL/6 mice were studied following acute injection (1.5–15 mg) and chronic infusion (50 µg·day −1 , 14 days). RESULTS In macrophages, 5αTHB increased secretion of IL‐10 similarly to corticosterone (180%, 340%; data are % vehicle, treated with 5αTHB and corticosterone, respectively) and suppressed LPS‐induced secretion of TNF‐α (21.9%, 74.2%) and IL‐6 (16.4%, 69.4%). In mice with thioglycollate‐induced peritonitis, both 5αTHB and corticosterone reduced the numbers of neutrophils (58.6%, 49.9%) and inflammatory monocytes (69.5%, 96.4%), and also suppressed MCP‐1 (48.7%, 80.9%) and IL‐6 (53.5%, 86.7%) in peritoneal exudate. In mice chronically infused with 5αTHB and corticosterone LPS‐induced production of TNF‐α from whole blood was suppressed to the same degree (63.2%, 37.2%). However, in contrast to corticosterone, 5αTHB did not induce body weight loss, increase blood pressure or induce hyperinsulinaemia. CONCLUSIONS 5αTHB has anti‐inflammatory effects in vitro and in vivo . At doses with equivalent anti‐inflammatory efficacy to corticosterone, 5αTHB did not induce metabolic toxicity and thus may be a prototype for a safer anti‐inflammatory drug.