Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids

IL-12 is a prominent Th1 differentiator and leukocyte activator. Ample studies showed suppression of IL-12 production by numerous stress factors, including prostaglandins, catecholamines, glucocorticoids, and opioids, but did so in vitro and in the context of artificial leukocyte activation, not simulating the in vivo setting. In a recent study we reported in vivo suppression of plasma IL-12 levels by behavioral stress and surgery. The current study aims to elucidate neuroendocrine mechanisms underlying this phenomenon in naïve F344 rats. To this end, both adrenalectomy and administration of specific antagonists were used, targeting the aforementioned stress factors. The results indicated that corticosterone and prostaglandins are prominent mediators of the IL-12-suppressing effects of stress and surgery, apparently through directly suppressing leukocyte IL-12 production. Following surgery, endogenous prostaglandins exerted their effects mainly through elevating corticosterone levels. Importantly, stress-induced release of epinephrine or opioids had no impact on plasma IL-12 levels, while pharmacological administration of epinephrine reduced plasma IL-12 levels by elevating corticosterone levels. Last, a whole blood in vitro study indicated that prostaglandins and corticosterone, but not epinephrine, suppressed IL-12 production in non-stimulated leukocytes, and only corticosterone did so in the context of CpG-C-induced IL-12 production. Overall, the findings reiterate the notion that results from in vitro or pharmacological in vivo studies cannot indicate the effects of endogenously released stress hormones under stress/surgery conditions. Herein, corticosterone and prostaglandins, but not catecholamines or opioids, were key mediators of the suppressive effect of stress and surgery on in vivo plasma IL-12 levels in otherwise naïve animals. © 2014 Elsevier Ltd.