Differential effects of estradiol on the adrenocorticotropin responses to interleukin-6 and interleukin-1 in the monkey

Endotoxin and the inflammatory cytokines interleukin (IL)-1 and IL-6 are po tent activators of the hypothalamic-pituitary-adrenal (HPA) axis. Although estradiol (E-2) has been shown to enhance the HPA response to certain types of stress, previous studies in the rodent have shown that HPA responses to endotoxin and to IL-1 were enhanced by ovariectomy and attenuated by E-2. The mechanisms underlying these observations are unclear, but there is evid ence that E-2 may have direct inhibitory effects on IL-6 synthesis and rele ase. Because endotoxin and IL-1 both stimulate IL-6, it is possible that th e E-2-induced suppression of the HPA response to endotoxin and IL-1 results from decreased IL-6 release. We have therefore examined the ACTH response to IL-6 and IL-1 beta in six ovariectomized rhesus monkeys with and without 3 weeks off, replacement. In the first study, plasma ACTH levels peaked at 60 min after iv injection of 6 mug recombinant human IL-6. Both the ACTH r esponse, over time, and the area under the ACTH response curve were signifi cantly higher in the E-2-treated animals (P < 0.05). The peak ACTH level wa s 66 +/- 16 pg/ml without E-2 vs. 161 +/- 69 pg/ml with E-2. In the second study, iv infusion of recombinant human IL-1 beta (400 ng) produced plasma IL-6 levels comparable with those seen after IL-6 injection in the first st udy. In the IL-1 study, however, there was a significant attenuation of the ACTH response, over time, in the E-2-treated animals (P < 0.001); the peak ACTH level was 83 +/- 34 pg/ml us. 13 +/- 4.4 pg/ml after E,. The IL-6 res ponse was similarly attenuated (P < 0.001); the peak IL-6 level was 614 +/- 168 pg/ml us. 277 +/- 53 pg/ml after E-2 treatment. Our results demonstrat e that physiological levels of E, enhance the ACTH response to IL-6 but att enuate the ACTH response to IL-1. The attenuated ACTH response to IL-1 was accompanied by a blunted IL-6 response. Our results suggest that the blunte d HPA response to IL-1 can be explained, at least in part, by E-2-induced a lterations in IL-6 release. It remains to be determined whether E, affects other inflammatory mediators that also participate in this process.