Stress-Induced Glucocorticoid Release Upregulates Uncoupling Protein-2 Expression and Enhances Resistance to Endotoxin-Induced Lethality

Neuroimmunomodulation. 2015;22(5):279-92. doi: 10.1159/000368802. Epub 2015 Jan 28.

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.

Methods/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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Cell Line, Transformed
  • Corticosterone / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Glucocorticoids / metabolism*
  • Ion Channels / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism*
  • Nitric Oxide / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor, Melanocortin, Type 2 / deficiency
  • Receptor, Melanocortin, Type 2 / genetics
  • Stress, Psychological / metabolism*
  • Uncoupling Protein 2
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*

Substances

  • Cytokines
  • Glucocorticoids
  • Ion Channels
  • Lipopolysaccharides
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Receptor, Melanocortin, Type 2
  • Ucp2 protein, mouse
  • Uncoupling Protein 2
  • Nitric Oxide
  • Adrenocorticotropic Hormone
  • Corticosterone