title: Stress-Induced Glucocorticoid Release Upregulates Uncoupling Protein-2 Expression and Enhances Resistance to Endotoxin-Induced Lethality.
abstract: OBJECTIVE
  Although psychological and/or physiological stress has been well documented to influence immune responses, the precise mechanism for immunomodulation remains to be elucidated. The present work describes the role of the hypothalamic-pituitary-adrenal (HPA) axis in the mechanism of stress-mediated enhanced-resistance to lethality after lipopolysaccharide (LPS) injection.
  
  
  RESULTS
  Preconditioning with restraint stress (RS) resulted in enhanced activation of the HPA axis in response to LPS injection and suppressed LPS-induced release of proinflammatory cytokines and nitric oxide metabolites. Melanocortin 2 receptor-deficient mice (MC2R(-/-)) failed to increase plasma levels of glucocorticoids in response to LPS injection, and exhibited high sensitivity to LPS-induced lethality with enhanced release of proinflammatory cytokines as compared with MC2R(+/-) mice. Real-time PCR analysis revealed that RS induced upregulation of uncoupling protein-2 (UCP2) in macrophages in the lung and the liver of MC2R(+/-), but not of MC2R(-/-), mice. In addition, RS increased UCP2-dependent uncoupling activity of isolated mitochondria from the liver of MC2R(+/-), but not of MC2R(-/-), mice. In vitro study revealed that corticosterone and dexamethasone directly increased UCP2 expression in mouse RAW 264.7 macrophages and suppressed the generation of LPS-induced mitochondrial reactive oxygen species (ROS) and TNF-α production. Knockdown of UCP2 by small interfering RNA blunted the dexamethasone action for suppressing LPS-induced mitochondrial ROS and TNF-α production.
  
  
  CONCLUSIONS
  The present work suggests that RS enhances activation of the HPA axis to release glucocorticoids and upregulation of UCP2 in macrophages, thereby increasing the resistance to endotoxin-induced systemic inflammation and death.
authors.affiliation: Department of Physiology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Kasahara
authors.forename: Atsuo
authors.initials: A
authors.lastname: Sekiyama
authors.forename: Mika
authors.initials: M
authors.lastname: Hori
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kuratsune
authors.forename: Naoki
authors.initials: N
authors.lastname: Fujisawa
authors.forename: Dai
authors.initials: D
authors.lastname: Chida
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hiramoto
authors.forename: Jiawei
authors.initials: J
authors.lastname: Li
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Masayasu
authors.initials: M
authors.lastname: Inoue
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kitagawa
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D003345:Corticosterone / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D044103:Receptor, Melanocortin, Type 2 / Q000172:deficiency / Q000235:genetics; D013315:Stress, Psychological / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D044103:Receptor, Melanocortin, Type 2; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D009569:Nitric Oxide; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone