MODULATORY EFFECTS OF GLUCOCORTICOIDS AND CATECHOLAMINES ON HUMAN INTERLEUKIN-12 AND INTERLEUKIN-10 PRODUCTION - CLINICAL IMPLICATIONS

Interleukin-12 (IL-12) is a key inducer of differentiation of uncommit ted T helper (TH) cells toward the TH1 phenotype, which regulates cell ular immunity, whereas IL-10 inhibits TH1 functions and potentiates TH 2-regulated responses (i.e., humoral immunity). To examine the potenti al effects of stress on TH1/TH2 balance, we studied the ability of thr ee prototype stress hormones-dexamethasone (a synthetic glucocorticoid ) and the catecholamines norepinephrine and epinephrine-to alter the p roduction of IL-12 (p70) and IL-10 induced by bacterial lipopolysaccha ride (LPS) in human whole blood. Dexamethasone inhibited LPS-induced b ioactive IL-12 production in a dose-dependent fashion and at physiolog ically relevant concentrations; it had no effect on IL-10 secretion. T he glucocorticoid-induced reduction of IL-12 production was antagonize d by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was mediated by the glucocorticoid receptor. Norepinephrine and epinep hrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations; both catecholamines, however, dose-d ependently increased the production of IL-10. The effects of either ca techolamine on IL-12 or IL-10 secretion were blocked completely by pro pranolol, a beta-adrenoreceptor antagonist, indicating that they were mediated by the beta-adrenergic receptor. These findings suggest that the central nervous system may regulate IL-12 and IL-10 secretion and, hence, TH1/TH2 balance via the peripheral end-effecters of the stress system. Thus, stress may cause a selective suppression of TH1 functio ns and a shift toward a TH2 cytokine pattern rather than generalized T H suppression. The TH1-to-TH2 shift may be responsible for the stress- induced susceptibility of the organism to certain infections. Through the same or a reciprocal mechanism, states associated with chronic hyp eractivity or hypoactivity of the stress system might influence the su sceptibility of an individual to certain autoimmune, allergic, infecti ous, or neoplastic diseases.