DIFFERENTIAL-EFFECTS OF CENTRAL AND PERIPHERAL INJECTION OF INTERLEUKIN-1-BETA ON BRAIN C-FOS EXPRESSION AND NEUROENDOCRINE FUNCTIONS

Cytokines such as interleukin-1-beta (IL-1-beta) alter the activity of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in the rat. However, the brain sites at which IL-1-beta exerts these effects have not been well identified. The present study sought to identify some of these sites, using c-fos protein expression as an index of cellular activation. We also attempted to determine possible differences between the effects of peripheral and central injection of IL-1-beta on the activation of specific brain areas. Castrated male rats received intravenous (i.v.) or intracerebroventricular (i.c.v.) injections of IL-1-beta through a jugular catheter or a permanent cannula implanted in the right lateral ventricle, respectively. Blood samples were taken before, as well as 30 and 120 min after i.v. or i.cv. IL-1-beta infusion in order to measure plasma ACTH and LH levels. Immediately thereafter, the rats were anesthetized with pentobarbital, then perfused. Their brains were removed and postfixed for one hour. Thirty-mu-m frozen sections were cut and approximately every fourth tissue section was processed for c-fos expression by an avidin-biotin-peroxidase method. Both i.v. (1-mu-g) and i.c.v. (100 ng) injection of IL-1-beta significantly increased plasma ACTH levels, but only i.c.v. treatment measurably inhibited LH secretion. I.c.v. infusion of the cytokine markedly augmented c-fos expression in the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the hypothalamus. A large amount of CRF cells in the PVN contained labelled c-fos protein (as measured by a double labelling technique), which indicates that CRF perikarya in this hypothalamic region are activated by the central administration of IL-1-beta. In contrast, i.v. injection of IL-1-beta did not significantly alter c-fos expression in the PVN or the ARC of the hypothalamus. These results suggest that the increased HPA axis activity which follows the peripheral IL-1-beta administration, a phenomenon previously shown to depend on endogenous CRF, does not require immediate activation of hypothalamic CRF perikarya. Thus our results indicate that the stimulatory effect of blood-born cytokine may be exerted at the level of nerve terminals in the median eminence. In contrast, i.c.v.-injected IL-1-beta appears to activate the HPA axis through a stimulation of CRF neurons within the parvocellular part of PVN. Finally, we postulate that the increase in cellular activity observed in the ARC of the hypothalamus may be involved in the decrease in LH secretion observed after i.c.v. infusion of IL-1-beta.