Glucocorticoid-induced type 1 type 2 cytokine alterations in humans: A model for stress-related immune dysfunction

Increased psychologic and physiologic stressors can have profound effects o n the immune system. Previously believed to be immunosuppressive, there is mounting evidence that stress may actually induce a shift in the type 1/typ e 2 cytokine balance toward a type 2 cytokine response. Cortisol is elevate d in response to stress and has been reported to alter cytokine production in murine and human peripheral blood mononuclear cells (PBMC). The current investigation examined the effects of dexamethasone (DEX) mimicking basal, stress, and supraphysiologic levels of cortisol on production of interferon -gamma (IFN-gamma) (type-1), interleukin (IL)-12p40 (type 1), IL-10 (type 2 ), and IL-4 (type 2) by human PBMC. Both supraphysiologic and stress levels of DEX decreased production of type 1 cytokines and either increased or ma intained production of type 2 cytokines PBMC stimulated with phytohemagglut inin (PHA), immobilized anti-CD3, lipopolysaccharide (LPS) or tetanus. Alth ough preincubation with DEX was sufficient to induce a type 2 switch in sho rt-term mitogen cultures, PBMC cultures for extended periods of time requir ed DEX at the initiation and throughout the duration of culture. Mifepristo ne, a glucocorticoid receptor antagonist, blocked the DEX-induced shift in the type 1/type 2 cytokine balance. These data demonstrated the ability of the glucocorticoid dexamethasone, to induce a shift in the type 1/type 2 cy tokine balance toward a type 2 cytokine response and simulate the type 1/ty pe 2 cytokine alterations observed in in vivo stress models. This model wil l allow detailed investigation of the cellular and molecular mechanisms of stress-induced immune alterations in humans.