Interactions between tumor necrosis factor-α, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat

We studied the effects of tumor necrosis factor-α (TNFα), 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 TNFα 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 TNFα injections. This suggested that CRH is a major mediator of the HPA axis response to TNFα. We subsequently evaluated the ability of TNFα 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 TNFα (10 pM to 1 μM). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an ECB0 of 6.7 x 10 pM (P < 0.05). Preincubation of hypothalamic expiants with dexamethasone, indomethacin (1 μM), eicosatetraynoic acid (10 μM), or nordihydroguaiaretic acid (30 μM) resulted in inhibition of TNFα-stimulated CRH secretion (P < 0.05). Interestingly, 4-h incubation with TNFα had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNFα (100 nM and 1 μM), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNFα 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 eicos-anoid mediated. The primary site of action of TNFα appears to be the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNFα, however, cannot be excluded.