Blockade by lnterleukin-1-Alpha of Nitricoxidergic Control of Luteinizing Hormone-Releasing Hormone Release in vivo and in vitro

Abstract

Nitric oxide (NO) synthase (NOS), the enzyme that converts arginine into citrulline plus NO, the latter a highly active free radical, occurs in a large number of neurons in the brain, including certain neurons in the hypothalamus. Our previous experiments have shown that norepinephrine (NE)-induced prostaglandin E²(PGE²) release from medial basal hypothalamic explants (MBH) is mediated by NO. Because release of luteinizing hormone (LH)-releasing hormone (LHRH) is also driven by NE and PGE², we hypothesized that NO controls pulsatile release of LHRH in vivo, which in turn induces pulsatile LH release. Indeed, in vivo and in vitro experiments using an inhibitor of NOS (N^G-monomethyl-L-arginine; NMMA) demonstrated that pulsatile LH release is mediated by NO; LHRH release in vitro is also mediated by this free radical. Cytokines that are released from cells of the immune system during infection also inhibit LHRH release. We compared the action of one such cytokine, interleukin-1Α(IL-1Α), on LHRH release with that of substances which inhibit or induce NO release. Microinjection of IL-1Α(0.06 pmol in 2µl) into the third cerebral ventricle (3V) of conscious, castrated male rats had an action similar to that of 3V microinjection of NMMA (1 mg in 5µl): it blocked pulsatile LH, but not follicle-stimulating hormone (FSH) release. The only difference between the responses to NMMA and IL-1Αwas that the latency to onset was greater with IL-1Α. When both NMMA and IL-1Αwere microinjected together, there was an additive suppressive effect on LH release during the first hour after injection. As in the case of NMMA, there was no effect on pulsatile FSH release of IL-la injected alone or together with NMMA. The latter results suggest that hypothalamic control of FSH release is distinct from that of LH and does not involve NO. Previous in vitro experiments showed that IL-1Αalso has an action identical to that of NMMA; inhibition of NE-induced PGE²and LHRH release from MBH explants. Therefore, IL-1Αappears to act on its receptors on the NOergic neurons to prevent the release of NO, or on the LHRH terminals to inhibit the response to NO. To test the hypothesis that IL-1Αdirectly inhibits the response of LHRH terminals to NO, we incubated MBH explants with sodium nitroprusside (NP; 500µM)_twhich spontaneously releases NO. NP-induced LHRH release was inhibited by IL-1Α(10 pM).We conclude that IL-1Αdirectly suppresses the response of the LHRH terminals to NO.

Ethanol inhibits luteinizing hormone-releasing hormone (LHRH) secretion by blocking the response of LHRH neuronal terminals to nitric oxide.

“…This was made possible by the fact that NP, the releaser of NO, can directly cause the LHRH terminals to release LHRH. IL-la blocked the response of the LHRH terminals to NO (11). Because of the similarity in action of IL-1 and ethanol on LHRH, we wondered whether it also inhibits the response to NO of the LHRH terminals in the postulated pathway.…”

Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat.

“…LHRH is secreted into the hypophyseal portal vessels and reaches the gonadotropes of the anterior pituitary gland, thereby mediating the release of LH, which in turn activates steroid secretion from the gonads and induces ovulation (3). The release of LHRH is pulsatile and is thought to be driven by norepinephrine, which acts on hypothalamic nitricoxidergic (NOergic) neurons (4)(5)(6)(7). The NO diffuses to the LHRH terminals in the arcuate-median eminence region to release LHRH by activating guanylate cyclase and cyclooxygenase (6,8).…”

Impact of Therapeutic Strategies on Growth in Pediatric Inflammatory Bowel Disease

“…Animal data suggests that both undernutrition and systemic inflammation are principle contributors to this phenomenon [68] (Figure 1). Inflammatory cytokines such as TNF-α and IL-1α were shown to suppress gonadotropin-releasing hormone (GnRH) secretion [69,70] and impair end-organ responsiveness to circulating testosterone [70] hence delaying pubertal development. Inflammationinduced anorexia was shown to reduce leptin levels which in turn, affect fat mass and subsequently results in delay of puberty [71].…”