Psychological stress suppresses innate IFN-γ production via glucocorticoid receptor activation: Reversal by the anxiolytic chlordiazepoxide

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.