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 TNF alpha (10 pM to 1 microM). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 x 10 pM (P less than 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 microM), eicosatetraynoic acid (10 microM), or nordihydroguaiaretic acid (30 microM) resulted in inhibition of TNF alpha-stimulated CRH secretion (P less than 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 microM), 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 TNF alpha appears to by the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF alpha, however, cannot be excluded.

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

“…Sharp et al (1989) and van der Meer et al (1996) reported that human TNF-␣ administered either into the lateral cerebroventricle or directly into the median eminence has no effect on plasma ACTH levels. Conversely, these authors (Sharp et al, 1989;van de Meer et al, 1996), as well as others (Bernardini et al, 1990;Besedovsky et al, 1991;Watanobe and Takebe, 1992;Sharp and Matta, 1993), have reported marked ACTH secretagogue activity of human TNF-␣ when administered intravenously. The apparent difference between the effects of intracerebral mouse and human TNF-␣ on plasma ACTH concentration may reflect the differing pharmacological profiles of the two identified TNF receptors, TNF-R1 and TNF-R2.…”

“…increases hypothalamic secretion of CRF in vitro and in vivo, and passive immunoneutralization of CRF inhibits the elevation in plasma ACTH concentrations produced by each of these three cytokines Sapolsky et al, 1987;Uehara et al, 1987;Naitoh et al, 1988;Tsagarakis et al, 1989;Bernardini et al, 1990;Navarra et al, 1991;Watanobe et al, 1991;Watanobe and Takebe, 1992). In contrast, the participation of endogenous cytokines in inflammation-induced activation of the HPA axis has been less well studied and largely restricted to the study of ACTH responses to systemic administration of the bacterial cell wall product endotoxin [or lipopolysaccharide (LPS)] (Tilders et al, 1994).…”

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

“…57,58 In addition, as noted above, TNFalpha effects may be mediated by induction of downstream cytokines such as IL-1, which has been shown to have a behavioral profile similar to TNFalpha in open-field testing. [40][41][42] Finally, consideration should be given to the possibility that reduced host responses to viral infection in TNF-R1-KO mice may be responsible (in relatively non-specific fashion) for the reversal of anxiety-like behaviors in glucocorticoid-deficient, MCMV-infected animals.…”

Organization and Integration of the Endocrine System: The Arousal and Sleep Perspective

“…In addition, all three cytokines directly stimulate hypothalamic CRH secretion in vitro, an action that is also suppressed by glucocorticoids and prostanoid synthesis inhibitors. [107][108][109] There is evidence to suggest that IL-6, the main endocrine cytokine, plays the primary role in the immune stimulation of the human HPA axis. Thus, in humans, IL-6 is an extremely potent activator of the axis and lacks the vascular leak-promoting and hypotensive side effects of the other two inflammatory cytokines.…”