Tumor Necrosis Factor-.ALPHA. Mediates Endotoxin Induced Suppression of Gonadotropin-Releasing Hormone Pulse Generator Activity in the Rat.

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Abstract
Bacterial endotoxin lipopolysaccharide (LPS) is known to suppress gonadotropin secretion and this effect is assumed to be mediated by cytokines. In the present study, we examined whether LPS affected hypothalamic electrical activity associated with LH pulses, and whether tumor necrosis factor-alpha (TNF-alpha), a major cytokine induced by LPS, was involved in this process. Ovariectomized rats were fitted with chronically implanted electrode arrays in the mediobasal hypothalamus, and multiunit activity (MUA) was recorded under conscious, unrestrained conditions. Blood samples were withdrawn every 6 min through an indwelling atrial catheter or determining serum LH concentrations. Intravenous (i.v.) injection of LPS (1 microgram) suppressed characteristic increases (volleys) in MUA associated with LH pulses throughout the experimental period up to 5 h. This suppressive effect of LPS on MUA volleys was significantly attenuated by simultaneous intracerebroventricular (icv) injection of the antibody (50 ng) to TNF-alpha through an indwelling cannula in the lateral ventricle. These changes in MUA were faithfully reflected in the LH secretory pattern. Further, either i.v. (0.4-2 micrograms) or i.c.v. (20-250 ng) injection of TNF-alpha suppressed the frequency of MUA volleys and associated LH pulses in a dose-dependent manner. These results suggest that LPS leads to the suppression of gonadotropin-releasing hormone pulse generator activity through a mechanism involving TNF-alpha.

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