Protective effects of endotoxin in a rat model of chronic inflammation are accompanied by suppressed secretion of pro-inflammatory cytokines and biphasic alteration in hypothalamo-pituitary-adrenal axis activity.
We have previously demonstrated that Gram-negative bacterial endotoxin can exert long-term protective effects against the chronic inflammatory disease adjuvant arthritis in rats. The present study was designed to investigate the mechanisms and time-course of hypothalamo-pituitary-adrenocortical (HPA) axis activity and cytokine secretion underlying this phenomenon. Rats were injected with endotoxin (lipopolysaccharide) and blood was collected either 7 or 21 days later. Priming with endotoxin induced a biphasic alteration in secretion of adrenocorticotrophic hormone and corticosterone in response to a second injection of endotoxin, with decreased secretion observed after 7 days whereas robust secretion was observed at 21 days. Seven days following priming with endotoxin, plasma concentrations of pro-inflammatory cytokines interleukin (IL)-6 and interferon (IFN)-gamma were reduced by 90%, and tumour necrosis factor (TNF)-alpha by 70%, compared to saline-treated rats, whereas robust secretion of the anti-inflammatory cytokine IL-10 was maintained in both groups. A similar net change favouring an anti-inflammatory cytokine secretory milieu was also observed 21 days following priming with endotoxin. This study provides evidence that the long-term protective effects of endotoxin on inflammation are associated with a sustained reduction in secretion of pro-inflammatory cytokines. HPA axis hypoactivity at 7 days suggests that corticosterone is not involved in suppressing IL-6, IFN-gamma and TNF-alpha at this time point. Conversely, hypersecretion of corticosterone at 21 days may underlie synchronous suppression of IL-6 and IFN-gamma. These data provide novel insight into interactions between HPA axis activity and cytokine secretion following endotoxin priming prior to induction of inflammatory disease.
Richards
L J
LJ
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.
Chover-Gonzalez
A
A
Harbuz
M S
MS
Jessop
D S
DS
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005500:Follow-Up Studies; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000276:immunology*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone