Elenkov I J, Papanicolaou D A, Wilder R L, Chrousos G P
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Assoc Am Physicians. 1996 Sep;108(5):374-81.
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.
白细胞介素-12（IL-12）是未分化的T辅助（TH）细胞向TH1表型分化的关键诱导因子，可调节细胞免疫，而IL-10则抑制TH1功能并增强TH2调节的反应（即体液免疫）。为了研究应激对TH1/TH2平衡的潜在影响，我们研究了三种典型应激激素——地塞米松（一种合成糖皮质激素）以及儿茶酚胺去甲肾上腺素和肾上腺素——改变人全血中细菌脂多糖（LPS）诱导的IL-12（p70）和IL-10产生的能力。地塞米松以剂量依赖的方式并在生理相关浓度下抑制LPS诱导的生物活性IL-12产生；它对IL-10分泌没有影响。糖皮质激素受体拮抗剂RU 486可拮抗糖皮质激素诱导的IL-12产生减少，这表明其是由糖皮质激素受体介导的。去甲肾上腺素和肾上腺素也以剂量依赖的方式并在生理浓度下抑制IL-12产生；然而，两种儿茶酚胺均以剂量依赖的方式增加IL-10的产生。β-肾上腺素能受体拮抗剂普萘洛尔可完全阻断任一儿茶酚胺对IL-12或IL-10分泌的影响，表明它们是由β-肾上腺素能受体介导的。这些发现表明，中枢神经系统可能通过应激系统的外周终效应器调节IL-12和IL-10的分泌，从而调节TH1/TH2平衡。因此，应激可能导致TH1功能的选择性抑制并向TH2细胞因子模式转变，而不是普遍的TH抑制。TH1向TH2的转变可能是机体对应激诱导的某些感染易感性的原因。通过相同或相反的机制，与应激系统慢性亢进或减退相关的状态可能会影响个体对某些自身免疫性、过敏性、感染性或肿瘤性疾病的易感性。
