Interactions between Tumor Necrosis Factor-α, Hypothalamic Corticotropin-Releasing Hormone, and Adrenocorticotropin Secretion in the Rat*

Abstract

We studied the effects of tumor necrosis factor-.alpha. (TNF.alpha.), a macrophage-derived pleiotropic cytokine produced during the inflammatory/immune response, on the function of the hypothalamic-pituitary-adrenal (HPA) axis of the rat. Intravenous injections of TNF.alpha. stimulated plasma ACTH and corticosterone secretion in a dose-dependent fashion. This effect was inhibited by a rat CRH antiserum that was administered to the rats 1 h before the TNF.alpha. injections. This suggested that CRH is a major mediator of the HPA axis response to TNF.alpha.. We subsequently evaluated the ability of TNF.alpha. to influence CRH and ACTH secretion in vitro by explanted rat hypothalami in organ-culture and by dispersed rat anterior pituicytes in primary culture respectively. Hypothalami were incubated for 40 min with graded concentrations of TNFa (10 pM to 1 .mu.M). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 .times. 10 pM (P < 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 .mu.M), eicosatetraynoic acid (10 .mu.M), or nordihydroguaiaretic acid (30 .mu.M) resulted in inhibition of TNF.alpha.-stimulated CRH secretion (P < 0.05). Interestingly, 4-h incubation with TNF.alpha. had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNF.alpha. (100 nM and 1 .mu.M), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNF.alpha. represents one of the immune response mediators that directly or via stimulation of other cytokines act as activators of the HPA axis during immune/inflammatory reactions. This effect appears to be glucocorticoid suppressible and eicosanoid mediated. The primary site of action of TNFa appears to be the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF.alpha., however, cannot be excluded.