An integrative approach to the effect of interleukin-6 on adaptation to restraint stress in rats

[摘要] ENGLISH ABSTRACT: Bi-directional communication exists between HPA-axis activation and interleukin-6(IL-6). However, the relative contribution of centrally versus peripherally secreted IL-6 remains unclear, especially under psychological stress conditions. Wehypothesised that the HPA response to mild psychological stress is dependent on IL-6, both centrally and peripherally.120 male Wistar rats were divided into four groups, depending on whether theyreceived an anti-IL-6 antibody (Ab) (2μg/ml/kg body weight) or a placebo (sterilesaline) injection and whether or not they were subjected to 1 hour of restraint stressfor 1, 2 or 3 days. Rats were euthanized 24 hours after stress exposure.Plasma corticosteroid (GC) levels remained significantly increased 24 hours after asingle stress exposure (control placebo (CP) versus stress placebo (SP): p < 0.05).The undetectable plasma IL-6 levels evident across all groups may be explained bythe short half-life of IL-6. Plasma IL-1β levels decreased when IL-6 was blocked inunstressed animals (CP versus CAb: p < 0.05), suggesting a role for IL-6 in themaintenance of IL-1β levels under tonic physiological conditions.At tissue level, pituitary gland mass increased significantly at time point 2,independently of stress when blocking IL-6 (CAb: p < 0.05). This suggests that whennormal homeostasis is threatened, immediate adaption or at least compensationmay occur. It was observed that GR, IL-1β, IL-1βR, IL-6, IL-6R and GABAARα1showed no response to stress alone in the pituitary. It is therefore more likely thatresistance to adaptation exists centrally. IL-1β and IL-1βR (p < 0.05) andGABAARα1 (p < 0.005) expression increased in the CAb group in the pituitary, againsuggesting a role for IL-6 under control conditions. In terms of the adrenal, blocking IL-6 resulted in decreased glandular mass at time point 1, independent of stress(CAb and SAb: p < 0.005). The up-regulation in GR expression seen in CAb andSAb (p < 0.05) may be the effect of a compensatory mechanism to increase IL-6dependent bioactivity of GCs. The fact that expression of IL-6, IL-6R, IL-1β and IL-1βR consistently increased in the Ab groups, and mostly in the zona fasciculata andzona reticularis, suggests that lack of local direct negative cytokine feedbackoccurred in response to very low plasma IL-6 levels and that this contributes morethan GCs in the down-regulation of inflammatory cytokine release.In conclusion, consistent effects of the Ab were apparent in the tissues investigated,even in control conditions, suggesting that IL-6 plays a role in the maintenance ofbasal homeostasis, including its regulation of the response to psychological stress.We found differential regulation in terms of cytokines and GCs when comparingperipheral versus central effects of stress and Ab, as well as the levels of cytokinesin the blood compartment, compared to within tissues.

[发布机构] Stellenbosch University