Tumor Necrosis Factor a Inhibits the Hormonal Response of the Pituitary Gland to Hypothalamic Releasing Factors*

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Abstract
Tumor necrosis factor .alpha. (TNF.alpha.), a monokine produced by activated macrophages and monocytes, may be an essential mediator of the pathogenesis and of the hormonal response to endotoxic shock. It has been suggested that an elevated level of TNF.alpha. is a marker for morbidity and mortality during septic shock, and that treatment with antibodies against TNF.alpha. decreases mortality. Because monokines have been shown to interact at the hypothalamic-pituitary level, we have studied the effect of TNF.alpha. on basal and stimulated hormone release from normal rat anterior pituitary cells. After 3 days of incubation, primary cultures of rat anterior pituitary cells were stimulated with either 0.5 ng/ml CRF, 3 ng/ml AVP, 10 ng/ml angiotensin II (AII), 10-6 M TRF, 10-8 M LHRH, or 10-5 M GHRH, alone or in the presence of 20 or 50 ng/ml human or murine recombinant TNF.alpha.. The culture media were analyzed for ACTH, GH, LH, and PRL content. Each experiment was performed in triplicate and was repeated 3 to 8 times. Time-course experiments (n = 3) demonstrated that TNF.alpha. inhibited CRF-stimulated ACTH production over a period of 8, 16, and 24 h, but had no effect before a period of 4 h. At doses ranging from 1 to 100 ng/ml, TNF.alpha. did not affect basal ACTH secretion but inhibited CRF-stimulated ACTH release in a dose-dependent manner (ED50 .apprx. 10 ng/ml). At a dose of 50 ng/ml, TNF.alpha. inhibited AVP-stimulated ACTH release by 30% and blocked the effect of AII. TNF.alpha. (20 and 50 ng/ml) completely prevented the CRF-AVP potentiation of ACTH release. Similarly, TNF.alpha. inhibited the stimulated release of GH (100% inhibition), LH (35% inhibition), and PRL (100% inhibition). TNF.alpha. had no (35% inhibition), and PRL (100% inhibition). TNF.alpha. had no effect on the basal secretion of GH or LH but inhibited basal PRL in a dose-dependent manner. The administration of the monokine did not cause any cellular damage because 48 h after removal of the TNF.alpha. treatment the cells showed normal basal and stimulated hormone levels in response to their specific stimuli. Incubation of TNF.alpha. solutions with antibody to TNF.alpha. reversed all TNF.alpha. actions. These data suggest that TNF.alpha. inhibits the secretion of pituitary hormones and particularly suppress the response of the corticotroph cells. This inhibitory effect may contribute to the increased mortality observed in cases of severe septic shock with high circulating TNF.alpha. levels.