Role of Nitric Oxide in the Actions of Cytokines on Hypothalamic Releasing Hormone Secretion

Abstract

Interleukins act within the hypothalamus to cause the release of corticotropin-releasing hormone (CRH) and inhibit release of luteinizing hormone-releasing hormone (LHRH). Nitric oxide synthase (NOS), the enzyme that converts arginine into citrulline plus nitric oxide (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 in vivo experiments in rats employing NG-monomethyl-L-arginine (NMMA), an inhibitor of NOS and nitroprusside, a releaser of NO, have determined that interleukin-2 (IL-2) activates CRH release by acting on its receptors on cholinergic neurons which stimulate NOergic neurons by muscarinic receptors. The NO diffuses to the CRH neurons and activates them as revealed by in vitro experiments with hypothalamic explants. On the other hand, norepinephrine or glutamic acid activate LHRH release by stimulating NOergic neurons that in turn induce LHRH release by activation of guanylate cyclase and cyclooxygenase. IL-lα acts directly on the LHRH neuron to block its response to NO on the basis of in vitro experiments. In vivo, NO stimulates LHRH release which induces pulsatile LH but not FSH release on the one hand and induces mating behavior on the other. The IL-1 -induced blockade of LHRH release by NO may account for the reduction in libido in infection. In vivo experiments employing injection of NMMA into the 3rd ventricle have revealed that NO mediates the prolactin-releasing action of interleukins. It also mediates pulsatile growth hormone (GH) release via stimulation of growth hormone-releasing hormone (GRH) release. IL-1 inhibits pulsatile GH release by blocking the response of the GRH neurons to NO. IL-1 also stimulates somatostatin release.