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 uncommitted T helper (TH) cells toward the TH1 phenotype, which regulates cellular immunity, whereas IL-10 inhibits TH1 functions and potentiates TH2-regulated responses (i.e., humoral immunity). To examine the potential effects of stress on TH1/TH2 balance, we studied the ability of three prototype stress hormones-dexamethasone (a synthetic glucocorticoid) and the catecholamines norepinephrine and epinephrine-to alter the production of IL-12 (p70) and IL-10 induced by bacterial lipopolysaccharide (LPS) in human whole blood. Dexamethasone inhibited LPS-induced bioactive IL-12 production in a dose-dependent fashion and at physiologically relevant concentrations; it had no effect on IL-10 secretion. The glucocorticoid-induced reduction of IL-12 production was antagonized by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was mediated by the glucocorticoid receptor. Norepinephrine and epinephrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations; both catecholamines, however, dose-dependently increased the production of IL-10. The effects of either catecholamine on IL-12 or IL-10 secretion were blocked completely by propranolol, 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-effectors of the stress system. Thus, stress may cause a selective suppression of TH1 functions and a shift toward a TH2 cytokine pattern rather than generalized TH 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 hyperactivity or hypoactivity of the stress system might influence the susceptibility of an individual to certain autoimmune, allergic, infectious, or neoplastic diseases.
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
I J
IJ
Elenkov
D A
DA
Papanicolaou
R L
RL
Wilder
G P
GP
Chrousos
D000328:Adult; D001769:Blood / Q000378:metabolism*; D002395:Catecholamines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000502:physiology; D011433:Propranolol / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013564:Sympathetic Nervous System / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer
D002395:Catecholamines; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D016753:Interleukin-10; D018664:Interleukin-12; D015735:Mifepristone; D003907:Dexamethasone; D011433:Propranolol; D009638:Norepinephrine; D004837:Epinephrine