Hypothalamic action of cachectin to alter pituitary hormone release

Cachectin (tumor necrosis factor, TNF) is a macrophage hormone which is released during infection and after injection of bacterial lipopolysaccharides. We have already demonstrated that the peptide has direct action on the pituitary to alter pituitary hormone release in vitro. To evaluate its action in vivo, we injected it into the third ventricle (3V) of conscious, male rats and measured its effect on various anterior pituitary hormones. The peptide produced an elevation in rectal temperature measurable on first measurement at 1 hour postinjection which was maintained for 3 hours. The maximal increase in body temperature was 1-1.5°C and maximal effect was obtained by a dose as low as 1 ng (0.3 pmol) of the peptide. Preinjection of indomethacin into the 3V 1 hour prior to injection of TNF completely blocked the effect on body temperature without producing an alteration in rectal temperature itself which suggests that the elevation in body temperature may be mediated by prostaglandins. Following the intraventricular injection of various doses of TNF, there was no significant effect on plasma adrenocorticotropin (ACTH) except with the highest, 100 ng dose tested, which evoked a small but significant increase in plasma ACTH with a delay of 1 to 2 hours. Thus, the dose necessary to release ACTH was much higher than that required to elevate body temperature. The effect was no longer significant in indomethacin-pretreated animals suggesting a role for prostaglandins in the effect. This highest dose of intraventricularly administered TNF also produced a relatively modest, but significant, delayed increase in plasma GH. A delayed increase in plasma prolactin (Prl) occurred following both the 5 and 100 ng doses of intraventricular TNF, whereas there was a delayed and pronounced decrease in plasma thyrotropin (TSH) following these same doses. It is noteworthy that the dose required to produce alterations in any of the pituitary hormones was much higher than that required to elevate body temperature maximally suggesting a hypothalamic action independent of the temperature regulating centers. Since the sign of action of TNF in vivo following its intraventricular injection to effect pituitary hormone release was similar to that of its direct effects on pituitary hormone release in vitro in the case of ACTH, GH and Prl, we cannot exclude a direct pituitary site of action of the peptide to produce these effects: however, in view of the delay before hormonal changes occurred and the minute doses required, we believe that the effects are at the hypothalamic level. Since the effect of the peptide on TSH release was inhibitory following its intraventricular injection, whereas it had a stimulatory effect in vitro on release of TSH from pituitaries incubated in vitro, it is clear that the effect on TSH could not have been mediated on the pituitary directly. In conclusion, it is apparent that TNF has important actions both on the hypothalamus and the pituitary to alter pituitary hormone release which may play an important role in bringing about the pattern of pituitary hormone release which occurs during infection.