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Endocrinology Vol. 142, No. 7 2736-2741
Copyright © 2001 by The Endocrine Society

ARTICLES

Differential Effects of Estradiol on the Adrenocorticotropin Responses to Interleukin-6 and Interleukin-1 in the Monkey1

Ennian Xiao, Linna Xia-Zhang, Michel Ferin and Sharon L. Wardlaw

Departments of Medicine and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Endotoxin and the inflammatory cytokines interleukin (IL)-1 and IL-6 are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis. Although estradiol (E2) 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 E2. The mechanisms underlying these observations are unclear, but there is evidence that E2 may have direct inhibitory effects on IL-6 synthesis and release. Because endotoxin and IL-1 both stimulate IL-6, it is possible that the E2-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-1ß in six ovariectomized rhesus monkeys with and without 3 weeks of E2 replacement. In the first study, plasma ACTH levels peaked at 60 min after iv injection of 6 µg recombinant human IL-6. Both the ACTH response, over time, and the area under the ACTH response curve were significantly higher in the E2-treated animals (P < 0.05). The peak ACTH level was 66 ± 16 pg/ml without E2 vs. 161 ± 69 pg/ml with E2. In the second study, iv infusion of recombinant human IL-1ß (400 ng) produced plasma IL-6 levels comparable with those seen after IL-6 injection in the first study. In the IL-1 study, however, there was a significant attenuation of the ACTH response, over time, in the E2-treated animals (P < 0.001); the peak ACTH level was 83 ± 34 pg/ml vs. 13 ± 4.4 pg/ml after E2. The IL-6 response was similarly attenuated (P < 0.001); the peak IL-6 level was 614 ± 168 pg/ml vs. 277 ± 53 pg/ml after E2 treatment. Our results demonstrate that physiological levels of E2 enhance the ACTH response to IL-6 but attenuate 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 blunted HPA response to IL-1 can be explained, at least in part, by E2-induced alterations in IL-6 release. It remains to be determined whether E2 affects other inflammatory mediators that also participate in this process.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE INFLAMMATORY CYTOKINES interleukin (IL)-1, IL-6, and tumor necrosis factor-{alpha} are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis (1, 2). The resulting stimulation of adrenal glucocorticoid secretion exerts inhibitory effects on cytokine release and on the inflammatory process (3). Previous studies in the rodent have shown that estradiol (E2) can modulate the response of the HPA axis to inflammatory stimuli (4, 5). The effects of E2 on the HPA responses to endotoxin and to IL-1, however, are quite different from those on the HPA responses to other types of stress. Although E2 has been shown to enhance HPA responses to neurogenic and psychosocial stress (6, 7), HPA responses to endotoxin and to IL-1 were actually enhanced by ovariectomy and attenuated by E2 replacement (4, 5). The mechanisms underlying these observations are unclear but may involve gonadal steroid modulation of hypothalamic neuropeptides, of inflammatory mediators such as the cyclooxygenase or nitric oxide pathways, or of the inflammatory cytokines themselves. There is evidence that E2 may have direct inhibitory effects on IL-6 synthesis and release (8, 9, 10). Although tumor necrosis factor-{alpha}, IL-1ß, and IL-6 exert synergistic effects with respect to endotoxin-induced stimulation of the HPA axis, IL-6 plays a major role in this process, as indicated by the fact that antibodies against IL-6 almost completely block the ACTH response to endotoxin in mice (11). Because endotoxin and IL-1 both stimulate IL-6 (12), it is possible that the E2-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 [which does not stimulate IL-1 or tumor necrosis factor (TNF)-{alpha} release] and IL-1ß (which does stimulate TNF-{alpha} and IL-6 release) in six ovariectomized rhesus monkeys with and without 3 weeks of E2 replacement.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Six adult female rhesus monkeys (Macaca mulatta), weighing 5–7 kg, were used in these experiments. Monkeys were housed in individual cages in a temperature-controlled room (19-22 C) with a 12-h light, 12-h dark photocycle and were fed Purina Monkey Chow supplemented with fresh fruit daily. All animals were ovariectomized at least 2 months before the studies. All protocols were approved by the Columbia University Institutional Animal Care and Use Committee.

Experimental design
The night before each experiment, monkeys were briefly sedated with 4–7 mg/kg Ketamine (Parke-Davis, Morris Plains, NJ), and a catheter was placed in the femoral vein for blood collection. The animals were then seated in a primate chair, to which they had previously been adapted, and the experiment was performed the next morning.

In an initial dose-response study, animals were injected iv with 1.2 µg (n = 3), 6 µg (n = 4), and 30 µg (n = 4) recombinant human IL-6. Subsequently, the 6-µg dose (~1 µg/kg) was chosen for further study. Five monkeys were studied twice, without and with 3 weeks of E2 replacement (via sc implanted SILASTIC capsules, Dow Corning, Midland, MI). The mean plasma E2 level in the replaced animals was 49 ± 5.8 pg/ml. In the next experiment, the effect of recombinant human IL-1ß, 400 ng (~67 ng/kg), infused iv over 30 min, was studied in six monkeys, without and with 3 weeks of E2 replacement. We had previously shown that this dose of IL-1ß would produce plasma levels of IL-6 comparable with those measured after the 6-µg IL-6 injection (13). The mean plasma E2 level in the replaced animals was 66 ± 6.3 pg/ml. Each monkey was studied twice, in random order, with or without E2 replacement. All studies in the same animal were separated by at least 3 weeks.

IL-6 was donated by Dr. Mark Tepper (Ares-Serono Group, Randolph, MA). The endotoxin level was reported to be less than 1 Endotoxin Unit/mg. IL-1ß was purchased from Bachem, Torrance CA; the endotoxin level was reported to be less than 0.1 ng/µg IL-1ß.

Blood samples (4 ml) were collected at -60, -30, and 0 min before IL-6 or IL-1ß administration and then at 30-min intervals for the first 2.5 h and hourly for the next 3 h. Blood samples were centrifuged, and plasma was separated and stored at -20 C for cytokine and hormonal assays.

Hormone and cytokine assays
ACTH was measured by a two-site immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). Cortisol was assayed by solid-phase RIA (Diagnostic Products, Los Angeles, CA). IL-6 was measured by specific monoclonal sandwich immunoassay with a human enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN), which we have validated for use in the rhesus monkey (13). Assay sensitivity is 6 pg/ml for 50 µl plasma; this assay is not affected by the addition of the IL-6 soluble receptor. E2 was measured by a commercial solid-phase, chemiluminescent immunoassay (Immulite, Diagnostic Products).

Statistical analysis
The effects of IL-6 and IL-1ß injection on hormone and cytokine responses in both groups were analyzed by ANOVA with repeated measures. Statistical comparisons between +E2 and -E2 groups, over time, were performed using Bonferroni-Dunn post hoc analysis. Areas under the hormone and cytokine response curves (AUCs) were calculated by trapezoid analysis, and the responses in both groups were compared by paired Wilcoxon rank-sum test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ACTH and cortisol responses to IL-6
In an initial study, the ACTH and cortisol responses to 1.2, 6.0, and 30 µg IL-6 were examined. There was a significant stimulation of ACTH and cortisol release at all three doses (P < 0.001) (Fig. 1Go). The 6-µg dose was chosen for subsequent studies. The mean IL-6 level measured at 30 min after the 6-µg injection was 190 ± 27 (SEM) pg/ml.



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  		Figure 1. The ACTH and cortisol responses to different doses of IL-6, injected at time 0, are depicted above. There was a significant stimulation of ACTH and cortisol release into peripheral blood in response to all three doses of IL-6 (P < 0.001).

 
The effect of E2 on the ACTH and cortisol responses to 6 µg IL-6 is shown in Fig. 2Go. Both the ACTH response, over time, and the AUC for ACTH response were significantly higher in the E2-treated animals (P < 0.05). The peak ACTH level was 66 ± 16 pg/ml without E2 vs. 161 ± 69 pg/ml with E2. The AUC for ACTH was 5,274 ± 911 without E2 vs. 10,480 ± 3,910 with E2. The cortisol response, over time, and the AUC were not significantly different in the two groups. The peak cortisol level in the E2-treated animals was 74 ± 5.2 µg/dl at 2.5 h; this was greater than the level of 56 ± 3.4 µg/dl measured in the untreated animals at the same time point (P < 0.05).



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  		Figure 2. The effect of E2 on the ACTH and cortisol responses to IL-6 (6 µg), injected at time 0, into ovariectomized (OVX) monkeys, is shown above. Both the ACTH response, over time, and the AUC for ACTH response were significantly higher in the E2-treated animals (P < 0.05). Although the cortisol response, over time, and the AUC were not significantly different in the two groups, the peak cortisol level at 2.5 h in the E2-treated animals was greater than the level measured in the untreated animals at the same time point (P < 0.05).

 
ACTH, cortisol, and IL-6 responses to IL-1ß
IL-1ß stimulated the release of ACTH, cortisol, and IL-6 into peripheral blood in ovariectomized monkeys (Figs. 3Go and 4Go). There was a marked attenuation of the ACTH response, over time, in the E2-treated animals (P < 0.001). The peak ACTH level was 83 ± 34 pg/ml in the untreated animals vs. 13 ± 4.4 pg/ml after E2 treatment. The AUC for ACTH was 7549 ± 3288 without E2 and 1344 ± 399 after E2 treatment (P < 0.05). Cortisol increased significantly, over time, in both groups of animals; but there was no effect of E2 treatment on this response. Thus, cortisol seemed to be stimulated equally in both groups despite a relatively modest increase in ACTH in the E2-treated monkeys. The IL-6 response to IL-1ß was also significantly attenuated in the E2-treated animals (P < 0.001). The peak IL-6 level was 614 ± 168 pg/ml in the untreated animals vs. 277 ± 53 pg/ml after E2 treatment.



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  		Figure 3. The effect of E2 on the ACTH and cortisol responses to IL-1ß (400 ng), injected at time 0, into OVX monkeys, is shown above. The ACTH response was markedly attenuated in the E2-treated animals (P < 0.001). Cortisol increased significantly in both groups of animals, but there was no effect of E2 treatment on this response.

 


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  		Figure 4. The effect of E2 on the IL-6 response to IL-1ß (400 ng), injected at time 0, into OVX monkeys, is shown above. The IL-6 response was significantly attenuated in the E2-treated animals (P < 0.001).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we examined the ACTH responses to two proinflammatory cytokines, IL-6 and IL-1ß, in ovariectomized monkeys, in the presence and absence of physiological levels of E2, characteristic of the midfollicular phase of the menstrual cycle. Both cytokines were shown to stimulate ACTH release, but the ACTH response was differentially affected by E2 replacement. E2 was shown to enhance the ACTH response to IL-6 but attenuate the ACTH response to IL-1. Although E2 has previously been reported to differentially modulate the HPA response to neurogenic and inflammatory stimuli, this is the first demonstration of a differential response to two inflammatory stimuli.

Although gonadal steroids have previously been reported to modulate the response of the HPA axis to stress, the specific effects vary with gender and the type of stress employed (6, 7, 14, 15, 16, 17). The HPA response to stress has generally been reported to be higher in the female. In the rodent, the HPA responses to immobilization or footshock have usually been reported to be enhanced by E2 in the female and inhibited by testosterone in the male (6, 15). In the nonhuman primate, ACTH and cortisol levels were also shown to increase with E2 treatment (18, 19, 20). The mechanisms underlying these effects are still not entirely clear, but there is evidence that sex steroids modulate the expression of the hypothalamic ACTH-releasing factors, CRH and arginine vasopressin (15, 21, 22, 23, 24), and also seem to modulate glucocorticoid negative feedback within the brain (6, 15, 24). In both male and female rodents, however, although there are gender differences in the HPA responses to endotoxin and IL-1, the responses in both sexes were enhanced by gonadectomy and attenuated by sex steroid replacement. Castration was shown to enhance the adrenal response to endotoxin in male and female mice; this was reversed by testosterone or E2 replacement (4). Castration was also shown to enhance the ACTH and corticosterone response to IL-1ß in rats of both sexes (5, 25, 26). Thus, the effects of E2 on the HPA responses to endotoxin and to IL-1 are quite different from those on the HPA responses to other types of stress. The mechanisms underlying this observation are unclear, but at least one mechanism may involve modulation of cytokine responses by E2.

There is considerable evidence that E2 exerts direct inhibitory effects on IL-6 synthesis and release. E2 has been reported to inhibit both IL-6 secretion and IL-6 gene expression in bone marrow-derived stromal cells and osteoblasts from rodents and humans (8). There is evidence that E2 inhibits the human IL-6 gene through an estrogen-receptor-mediated indirect effect on IL-6 gene transcription (9, 10). Circulating IL-6 levels have also been reported to be lower in postmenopausal women receiving estrogen replacement (27). We have recently shown that the endotoxin-induced release of IL-6, TNF-{alpha}, and IL-1ra into peripheral blood in vivo is attenuated by E2 replacement in postmenopausal women (28). E2 has also been reported to inhibit TNF-{alpha} and IL-1ß release from peripheral mononuclear cells in postmenopausal women (29, 30, 31). In addition, ovariectomy has been reported to enhance endotoxin-induced TNF-{alpha} release in mice (4).

IL-6, IL-1, and TNF-{alpha} can each independently activate the HPA axis. All three cytokines are released from peripheral mononuclear cells in response to bacterial endotoxins and exert synergistic effects with respect to stimulation of the HPA axis (1, 12). Although there is some indication that these cytokines exert direct effects at the level of the pituitary and adrenal, there is considerable evidence that acutely, these cytokines act at the level of the hypothalamus to stimulate CRH release with subsequent pituitary-adrenal activation. IL-6 plays a major role in this process, as shown by the fact that antibodies against IL-6 almost completely blocked the ACTH response to endotoxin in mice (11). In addition, IL-6-deficient mice have blunted corticosterone responses to endotoxin (32). IL-1 also stimulates the release of IL-6 and TNF-{alpha}. Because endotoxin and IL-1 both stimulate IL-6 and TNF-{alpha} (1), there is a question of whether the E2-induced suppression of the HPA responses to endotoxin and IL-1 results solely from decreased IL-6 and/or TNF-{alpha} release or whether other mediators are involved. In this study, we have therefore compared the HPA responses to IL-6 (which stimulates hypothalamic CRH without stimulating IL-1ß or TNF-{alpha}) with IL-1ß (which also stimulates IL-6 and TNF-{alpha} release). E2 was shown to enhance the ACTH response to IL-6 in ovariectomized monkeys. This is in agreement with previous studies in the monkey, showing a positive effect of E2 on the HPA axis (18, 19, 20), and in the rodent, showing an enhancement of the HPA response to neurogenic and psychogenic stress (6). Potential mechanisms underlying this effect may involve both modulation of the ACTH-releasing factors, CRH and arginine vasopressin (15, 21, 22, 23, 24), by E2 and modulation of glucocorticoid negative feedback within the brain by E2 (6, 15, 24). In contrast to IL-6, E2 had the opposite effect on the ACTH response to IL-1ß. This is in agreement with previous studies in the rodent, examining the effects of E2 on the HPA responses to IL-1ß and endotoxin (4, 5). Despite the marked attenuation of the ACTH response to IL-1ß by E2, cortisol seemed to be stimulated equally in both groups of monkeys. It should be noted, however, that baseline cortisol levels were already equally increased in both groups of monkeys, presumably because of the stress of chairing. In this setting, even a small increase in ACTH may be able to evoke a large adrenal response. Alternatively, it is possible that IL-1ß may act directly at the level of the adrenal to enhance the cortisol response. Several in vitro studies have demonstrated that IL-1ß can directly stimulate adrenal glucocorticoid secretion (33, 34, 35). However, most of these in vitro studies required prolonged incubation with IL-1ß to demonstrate an effect on glucocorticoid release and thus are unlikely to explain the rapid in vivo effects of IL-1ß on the HPA axis after a single injection. The effect of E2 on the ACTH response to IL-1ß in the monkey is also in agreement with our recent study in postmenopausal women, showing that E2 replacement attenuates the ACTH response to endotoxin (28). In the human study, a significant attenuation of the cortisol response was also noted. Baseline cortisol levels were much lower, however, in the human (compared with the monkey) study. It is of note that the attenuated ACTH response to IL-1ß in the E2-replaced monkeys was accompanied by a parallel decline in the IL-6 response. A similar decrease in plasma IL-6 levels, in response to endotoxin, was seen in the E2-replaced postmenopausal women.

In the castrated male rat, testosterone has been reported to attenuate the ACTH and corticosterone responses to IL-6 (36). Thus, in the male rat, testosterone has a similar effect on the HPA responses to neurogenic and psychogenic stresses, as well as on the HPA responses to IL-6, IL-1ß, and endotoxin. In contrast, our studies in the female monkey show that E2 enhances the ACTH response to IL-6. A similar enhancement by E2 has been reported for the ACTH response to neurogenic and psychogenic stresses in female rodents. These studies would suggest that gonadal steroid modulation of the HPA responses to nonimmune types of stress and to IL-6 may involve similar mechanisms. The marked difference in the effects of E2 on the ACTH responses to IL-1ß and IL-6 in the monkey indicates that an additional factor must be involved in modulating the responses to these two cytokines. One potential factor is the E2-induced suppression of IL-6 release. It should be noted that in the male, androgens have also been shown to suppress IL-6 production by monocytes and bone marrow-derived stromal cells (37, 38, 39). In addition, both testosterone and dihydrotestosterone have been shown to inhibit IL-6 gene expression (37). Thus, both androgens and estrogens can exert inhibitory effects on IL-6. This would be consistent with the inhibitory effects of testosterone and E2 on the HPA responses to IL-1ß and endotoxin, which have been reported in male and female animals, respectively.

Although our results suggest that the E2-induced attenuation of IL-6 release may contribute to the blunted ACTH response to IL-1ß in the monkey, it is likely that E2 affects other neuropeptides or inflammatory mediators that also participate in this process. E2 is known to affect CRH expression in the hypothalamus (21, 23, 24) (40). There is also evidence that although IL-1ß and IL-6 can both stimulate CRH, these two cytokines may differentially activate regions of the hypothalamus involved with CRH synthesis and release (41). Other studies in the rodent show that cytokine-induced activation of the HPA axis can be blocked by inhibitors of the cyclooxygenase pathway and enhanced by inhibitors of NO synthesis, indicating a role for PGs and NO in this process (42, 43, 44). Thus, there is evidence that endogenous NO restrains the HPA response to inflammatory stimuli. There is also evidence that E2 may stimulate NO production (45, 46). It is possible that the E2-induced stimulation of NO could contribute to the suppressed HPA response to inflammatory stimuli. However, blockade of NO formation with the NO synthase inhibitor, L-NAME, has been shown to augment the ACTH response to both IL-1ß and IL-6 (43). Thus, it is unlikely that the effects of E2 on NO can account for the different ACTH responses to IL-1ß and IL-6 that we see in E2-replaced monkeys.

In summary, our results demonstrate that physiological levels of E2 enhance the ACTH response to IL-6 but attenuate the ACTH response to IL-1ß in the monkey, indicating that different mechanisms are involved in at least some aspects of the HPA response to these two inflammatory cytokines. The attenuated ACTH response to IL-1ß was accompanied by an attenuated IL-6 response. Our results suggest that the blunted HPA response to IL-1ß can be explained, at least in part, by E2-induced alterations in IL-6 release. It remains to be determined whether E2 affects other inflammatory mediators that also participate in this process. These data also show that a physiological dose of estrogen can restrain the cytokine response to an inflammatory challenge in the primate in vivo. Inflammatory cytokines have been implicated in the pathogenesis of autoimmune and inflammatory diseases, as well as osteoporosis and cardiovascular disease (47, 48, 49). Within the brain, cytokine interactions have also been implicated in the pathogenesis of head injury, AIDS dementia complex, and Alzheimer’s disease (50). Because a protective effect of estrogen has been demonstrated in a number of these conditions, it remains to be determined whether this may, in part, be related to estrogen-induced changes in cytokine activity.


   Acknowledgments
 
The technical assistance of Mrs. Irene Conwell is greatly appreciated.


   Footnotes
 
1 This work was supported by NIH Grant MH-55708. Back

Received January 4, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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