INTERLEUKIN-1-BETA INHIBITS THE ENDOGENOUS EXPRESSION OF THE EARLY GENE C-FOS LOCATED WITHIN THE NUCLEUS OF LH-RH NEURONS AND INTERFERES WITH HYPOTHALAMIC LH-RH RELEASE DURING PROESTRUS IN THE RAT

The ability of central interleukin-1beta (IL-1beta) administration to modulate the hypothalamic LH-RH release as well as the endogenous expression of the c-fos protein located within the nucleus of LH-RH neurons was examined during the afternoon of proestrus in rats. In a first series of experiments, 50 or 100 ng IL-1beta were infused into the lateral ventricle of the rat brain at either 08.30, 12.00, 14.30, or 17.00 h of proestrus. The animals were then perfused transcardially with a solution of 4% paraformaldehyde from 17.30 and 18.00 h. In a second series of experiments, the rats were equipped with an intracerebroventricular (i.c.v.) cannula in the lateral ventricle and a push-pull cannula into the median eminence (ME), and LH-RH secretion was measured during the afternoon of proestrus. The third experiment investigated the putative role of corticotropin-releasing factor (CRF) in modulating the inhibitory effect of IL-1beta on LH secretion by infusing CRF antagonists before the i.c.v. administration of the cytokine to gonadectomized male and female rats. The central infusion of 50 or 100 ng IL-1beta at 12.00 h completely blocked the spontaneous expression of c-fos protein which normally occurs in the nucleus of LH-RH neurons between 17.30 and 18.00 h on proestrus. In contrast, 50 ng IL-1beta was less effective (P < 0.05) when administered at 08.30 h, and totally without effect when infused at 14.30 h. Infusion of 50 ng IL-1beta also markedly suppressed the hypothalamic release of LH-RH in proestrus rats bearing a push-pull cannula into the ME, and significantly decreased plasma LH levels in both gonadectomized male and female rats. Finally, we observed that the central administration of CRF antagonists did not modify the inhibitory effects of the cytokine on the activity of the hypothalamic-pituitary-gonadal (HPG) axis. These results provide the first direct evidence that IL-1beta is a potent inhibitor of LH-RH neuronal activity during the proestrus LH surge in intact cycling rats. As central administration of this cytokine completely inhibited the endogenous expression of c-fos protein within the nucleus of LH-RH neurons, our findings also suggest that IL-1beta acts at the level of LH-RH perikarya.