Role of Corticosterone in Immunosuppressive Effects of Acute Ethanol Exposure on Toll-Like Receptor Mediated Cytokine Production

Abstract

Acute ethanol (EtOH) exposure causes a stress response in humans, nonhuman primates, and rodents. Previous study results indicate that the suppression of some immunological parameters by EtOH is mediated in part or completely by elevated corticosterone concentrations induced by EtOH. However, initial results suggested that corticosterone is not involved in the modulation of cytokine production by macrophages in response to polyinosinic polycytidylic acid (poly I:C). New studies were conducted to further evaluate the role of corticosterone in EtOH-mediated changes in production of interleukin-6 (IL-6), IL-10, and IL-12 in serum and peritoneal fluid in mice treated with poly I:C or lipopolysaccharide (LPS). Suppression of IL-6, but not IL-12, production by EtOH was found to be mediated by corticosterone. However, poly I:C, LPS, and EtOH all caused similar elevations of corticosterone concentrations; thus, it is not clear if EtOH is required to induce levels or durations of corticosterone needed to mediate the observed effects. The situation with IL-10 was more complicated. Inhibition of corticosterone synthesis with aminoglutethimide prevented the increase in IL-10 production caused by EtOH plus poly I:C as compared to poly I:C only. This indicates that this increase is dependent on corticosterone, but exogenous corticosterone plus poly I:C did not increase IL-10 production. Thus, EtOH and corticosterone are required. However, with LPS inhibition of corticosterone synthesis (using aminoglutethimide) or inhibition of its action (using mifepristone) further increased, or did not affect IL-10 concentrations, suggesting fundamental differences in the signaling pathways leading from poly I:C and LPS to IL-10 production.

The role of glucococorticoids in the immediate vs. delayed effects of acute ethanol exposure on cytokine production in a binge drinking model

“…This indicates the initial effects of ethanol on the cells that produce these cytokines and chemokines are not sufficient to inhibit production of most cytokines and chemokines unless the corticosterone associated with poly I:C administration is present. Inhibiting corticosterone production 1hr before poly I:C did not affect poly I:C induced production of most cytokines, as we reported before [1, 3]. Thus, both ethanol exposure and elevated corticosterone from poly I:C exposure are required for the persistent inhibitory effects of ethanol (-12hrs) on most cytokine reduction.…”

“…Thus, the role of estrogen (or testosterone) in the differential responses of male and female mice to aminoglutethimide in the present study remains unclear. The similarities we have previously noted in the effects of aminoglutethimide, RU486, and adrenalectomy in female mice [1, 2] suggest that corticosterone is the major factor in the effects of these agents. However, differences in the effects of altered corticosterone responses in aminoglutethimide-treated male and female mice suggest that some interaction with sex hormones occurs.…”

“…It is interesting to note that of the cytokines tested in our lab, IL-6 demonstrated significant differences in serum levels induced by poly I:C in females when ethanol was administered 12 or 24 hours before poly I:C. Interleukin-6 has been shown previously to be regulated by endogenous glucocorticoids [1, 8, 32]. Therefore, it was not surprising that long after ethanol had been cleared from the body, the remaining effects on IL-6 levels in serum appeared to be mediated by corticosterone in the female mouse experiment.…”

“…Results from many studies indicate that acute ethanol exposure suppresses proinflammatory cytokine production when administered just before a stimulus, such as TLR ligands or bacteria [1-4] Research in our lab has indicated that this suppression is not primarily mediated by glucocorticoids produced as a result of the neuroendocrine stress response [2]. However, fewer studies have investigated the effects of acute ethanol exposure on cytokine production when administered 12 or more hours before stimulation [5].…”

Ultrastructural and hormonal modulations of adrenal gland with alterations of glycemic and liver glycogen profiles following arecoline administration in albino mice

“…Inhibition of corticosterone synthesis with aminoglutethimide prevents increase in IL-10 production caused by ethanol (54). But epinephrine increases a significant increase in the absolute number of total lymphocytes, T-helper (T H), T-suppressor (TS), natural killer (NK) cells and monocytes, 30 minutes after injection.…”