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Department of Pharmacology and Therapeutics Louisiana State University Health Sciences Center Shreveport, Louisiana 71130-3932
Address all correspondence and requests for reprints to: Dr. Adrian J. Dunn, Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, P.O. Box 33932, Shreveport, Louisiana 71130-3932. E-mail: adunn{at}lsuhsc.edu.
It is well established that certain proinflammatory cytokines have the ability to activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and there is widespread suggestive evidence that such cytokines may affect the axis at multiple levels. Silverman et al. (1) have now provided convincing evidence from in vivo studies that IL-6 can activate the HPA axis by actions on the hypothalamus, the pituitary, or directly on the adrenal cortex, and that these mechanisms are involved in the elevation of corticosterone in mice infected with murine cytomegalovirus (MCMV).
In the present study, they analyzed the mechanisms whereby MCMV elevates plasma ACTH and corticosterone, using combinations of treatments with antibodies to corticotropin-releasing factor (CRF), CRF-knockout mice, and hypophysectomy. Although pretreatment with an antibody to CRF prevented the plasma responses in ACTH and corticosterone to a swim stress, the corticosterone response to MCMV persisted, even though the treatment prevented the ACTH response. Similar robust corticosterone responses to MCMV were observed in CRF-knockout mice, although in this case, there was a small but significant increase in ACTH. The latter suggests that IL-6 may act directly on the pituitary to stimulate ACTH secretion. Interestingly, in both experiments, the corticosterone responses were accompanied by exaggerated increases in plasma IL-6 relative to infected wild-type animals.
Overall, these results suggest that IL-6 can act directly on the adrenal cortex to stimulate corticosterone secretion. The demonstration that MCMV markedly elevated plasma corticosterone in the absence of any increase in ACTH strongly supports this interpretation. This possibility is bolstered by the demonstration that a neutralizing antibody to IL-6 markedly attenuated the corticosterone response to MCMV. Finally, hypophysectomy prevented the MCMV-induced increases in ACTH and corticosterone, but with an enhanced increase in plasma IL-6. In the earlier experiments, IL-6 appeared to be able to act directly on the adrenals, so it was postulated that the lack of response occurred because ACTH was necessary to prime the adrenal cortex to respond to IL-6.
Although the concept that cytokines can activate the HPA axis is well founded, and there have been many prior suggestions that cytokines can act at the three major levels of the axis, the present in vivo studies provide the strongest evidence yet that under physiological conditions IL-6 can directly stimulate corticosteroid secretion from the adrenal cortex, as well as suggestive evidence that it can also stimulate ACTH secretion from the pituitary. These results supplement the many demonstrations of ACTH and corticosteroid secretion from isolated tissues in vitro [see reviews by Silverman et al. (2) and Dunn (3)], and reveal something of the circumstances in which such mechanisms may operate.
It is particularly interesting that when CRF function is compromised, plasma IL-6 concentrations are elevated. It would appear that this occurs to compensate for the lack of ACTH, but what is the mechanism of this increase in plasma IL-6? The present results reveal nothing of this mechanism, although it is likely that the lack of corticosteroid feedback suppressing IL-6 synthesis contributes to it. Nevertheless, it is important that in certain circumstances IL-6 can assume the function of ACTH, and possibly also of CRF.
These observations also suggest that elevation of circulating glucocorticoids is vital for an organism under threat from viral (and perhaps other) pathogens but is apparently less critical for physical or emotional stressors. The rationale for this is not clear, but perhaps it reflects the importance of elevated glucocorticoids in the regulation of immune responses to viral (and other) pathogens.
This multifunctional role for IL-6 may also be relevant to the early observations that immune activation activated the HPA axis (4). Administration to mice of Newcastle disease virus was shown to elevate plasma corticosterone, and Smith et al. (5) suggested that this ability was attributable to production of ACTH by immune cells. Unfortunately, the experiments reported in that study could not be replicated in animals in which the hypophysectomy was demonstrated to be complete (6, 7), excluding a role for ACTH from nonpituitary sources. The study of Silverman et al. (1), along with those of Bethin et al. (8) and Karalis et al. (9), show that activation of the HPA axis can be achieved in the absence of CRF, but that it is not immune cell-derived ACTH that is responsible, but rather IL-6. The IL-6, which may well be derived from immune cells, might act either as an ACTH-releasing factor at the pituitary, and/or directly on the adrenal cortex. However, the study of Silverman et al. (1) suggests that pituitary-derived ACTH may be necessary to prime the adrenal cortical cells for such a response.
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Received April 9, 2004.
Accepted for publication April 29, 2004.
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