Endocrinology, Vol 129, 384-388, Copyright © 1991 by Endocrine Society

ARTICLES

Stimulatory effect of interleukin-1 on adrenocorticotropin secretion in the rat: is it modulated by prostaglandins?

C Rivier and W Vale
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037.

The in vivo release of ACTH by interleukin-1 alpha (II-1 alpha) is reportedly blocked by acute treatment with indomethacin (indo), suggesting an involvement of endogenous prostaglandins in the effect of cytokines on the hypothalamic-pituitary-adrenal axis. However, indo also increases plasma corticosterone levels, raising the possibility that inhibition of ACTH release is due to suppressive effects of hypercorticolemia rather than to blockade of the stimulatory effects of II-1 alpha. We observed that the iv administration of indo (10 mg/kg) 15 min before II-1 alpha completely abolished the rise in plasma ACTH levels caused by the peripheral injection of this lymphokine to intact rats. At the time of II-1 alpha injection, plasma corticosterone levels were 39 +/- 12 ng/ml in controls and 121 +/- 22 ng/ml in indo-treated animals (P less than or equal to 0.01). In contrast, implantation of intact rats with indo pellets (which delivered 30 micrograms drug/h) 28 h before II-1 only partially interfered with II-1-induced ACTH secretion. In these rats plasma corticosterone levels before II-1 alpha injection were 29 +/- 14 ng/ml in controls and 66 +/- 18 ng/ml in rats implanted with indo pellets (P less than or equal to 0.05). To determine whether the effect of indo was due to corticosteroid feedback or represented a modulating action of prostaglandins themselves, a similar series of experiments was carried out in adrenalectomized rats. In the absence of corticoid replacement therapy, acute treatment with indo did not measurably interfere with the stimulatory effect of II-1 alpha. In contrast, indo blunted, but did not abolish, the effect of II- 1a in ADX rats pretreated with corticosterone or dexamethasone to normalize basal ACTH levels. We conclude that the acute ability of indomethacin to totally block II-1-induced ACTH secretion by intact rats appears to be primarily mediated through corticosteroid feedback. However, results obtained when a similar experiment was carried out in adrenalectomized/corticosteroid-treated rats suggest, although they do not prove, that the ability of II-1 alpha to activate the hypothalamic- pituitary-adrenal axis may be partially dependent on the release of prostaglandins.

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