title: Psychological stress suppresses innate IFN-gamma production via glucocorticoid receptor activation: reversal by the anxiolytic chlordiazepoxide.
abstract: Studies in humans and in animals indicate that psychological stress can modulate immune responses. Here we demonstrate that exposure to psychological stress (restraint stress) suppresses innate interferon (IFN)-gamma production in mice following an in vivo lipopolysaccharide (LPS) challenge. IFN-gamma signaling was also impaired by stress, as indicated by reduced STAT1 phosphorylation and reduced expression of the IFN-gamma-inducible genes, inducible nitric oxide synthase (iNOS) and IFN-gamma-inducible protein 10 (IP-10/CXCL10). Furthermore, restraint stress suppressed production of the IFN-gamma inducing cytokine interleukin (IL)-12 and increased production of the anti-inflammatory cytokine IL-10, which can inhibit both IL-12 and IFN-gamma production. However, using IL-10 knockout mice, we demonstrate that IL-10 does not mediate the suppressive effect of restraint stress on innate IFN-gamma production. Restraint stress increased corticosterone concentrations in serum and spleen, and consistent with a role for glucocorticoids in the immunosuppressive actions of stress, pre-treatment with the glucocorticoid receptor antagonist mifepristone completely blocked the stress-related suppression of innate IFN-gamma production. Addition of exogenous IL-12 to LPS-stimulated spleen cells reversed the suppressive effect of both restraint stress and corticosterone on IFN-gamma production. These data suggest that reduced IL-12 production is a key event in stress-induced suppression of innate IFN-gamma production. Finally, we demonstrate that pre-treatment with the anxiolytic drug chlordiazepoxide prevents the suppressive effect of stress on innate IFN-gamma production, and also attenuates the stress-induced increase in circulating corticosterone concentrations.
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: Curtin
authors.forename: Noreen T
authors.initials: NT
authors.lastname: Boyle
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D002707:Chlordiazepoxide / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006727:Hormone Antagonists / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000276:immunology / Q000378:metabolism*; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013315:Stress, Psychological / Q000276:immunology* / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D006727:Hormone Antagonists; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016753:Interleukin-10; D018664:Interleukin-12; D015735:Mifepristone; D002707:Chlordiazepoxide; D007371:Interferon-gamma; D003345:Corticosterone