Role of nitric oxide in interleukin 2-induced corticotropin-releasing factor release from incubated hypothalami.

Abstract

Stimulation of corticotropin-releasing factor (CRF) release from the hypothalamus by interleukin 2 (IL-2) was recently demonstrated. Cytokines induce nitric oxide synthase (NOS), an enzyme that converts L-arginine into L-citrulline and nitric oxide (NO). NO is believed to be responsible for the cytotoxic action of these agents. The constitutive form of NOS occurs in neurons in the central nervous system and NO appears to play a neurotransmitter role in cerebeilar and hippocampal function. We explored the probability that IL-2 and synaptic transmitters might release CRF via NO. The effects of L-arginine, the substrate for NOS, and NG_ monomethyl-L-arginine (NMMA), a competitive inhibitor of NOS, on IL-2-induced CRF release were studied using mediobasal hypothalami (MBHs) incubated in vitro in KrebsRinger bicarbonate buffer. L-Argoinue did not alter basal and IL-2-induced CRF release after 30 min of incubation but significantly elevated both basal and IL-2-induced CRF release when MBHs were incubated 30 min longer, presumably because the endogenous substrate had been depleted after the initial 30-min incubation period. In 30-min incubations, both carbachol, an acetylcholineomimetic drug, and norepinephrine stimulated CRF release. There was an additive effect of incubation of the MBHs in the presence of carbachol (10-7 M) and IL-2 (10-13 M). On the other hand, coincubation of MBHs with norepinephrine (10-6 M) and IL-2 (10-13 M) did not produce any additive effect. Addition of NMMA, an inhibitor of NOS, at 1 or 3 x 10-4 M completely suppressed IL-2-induced release of CRF as well as that caused by IL-2 plus carbachol. In contrast, the release of CRF induced by norepinephrine was not blocked by 3 x 10-4 M NMMA. The data indicate that IL-2 can activate constitutive NOS leading to increased NO release, which activates CRF release. It appears that NO is also involved in the release of CRF induced by carbachol but not by norepinephrine.Recent reports have demonstrated a stimulatory action of interleukin 2 (IL-2) on corticotropin-releasing factor (CRF) release using~ptoerfused hypothalami (1) or after static incubation with mediobasal hypothalami (MBHs) (unpublished data). In peripheral tissues, cytokines have been found to induce nitric oxide synthase (NOS), an enzyme that converts L-arginine (L-Arg) into L-citrulline and a reactive gas, nitric oxide (NO) (3, 4). The NO can induce cell death. It takes a number of hours for a cytokine to induce NOS. Consequently, this form of the enzyme has been termed the inducible NOS. A second type of NOS exists in a number of cells throughout the body, for example, in vascular endothelium, and it is termed the constitutive form of the enzyme (3, 4). In contrast to the inducible form, the constitutive form requires activation by an increase in intracellular calcium and its interaction with calmodulin. Both forms of NOS require L-Arg as the substrate (3, 4) and are inhibited by L-Arg analogues, such as NG-monomethyl-L-arginine (NMMA) (3, 4).The constitutive form of the enzyme ...

Interleukin (IL) 1β, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: Pathophysiological implications

“…This pattern of IL-1␤ and iNOS induction first in areas without an effective blood-brain barrier and later within brain parenchyma shows a temporal course by which endotoxin-induced inflammation can affect key functions of the brain. In addition to the direct effects of IL-1␤ on brain functions such as temperature regulation, food intake, sleep, and neuroendocrine regulation, IL-1␤ can further modulate CNS functions during inflammation through IL-1␤-induced iNOS, resulting in high levels of NO production that, for example, modulates release of corticotropin-releasing hormone (6,31). We also showed IL-1ra and IL-10 gene expression in the brain during these experiments.…”

Rapid nitric oxide‐ and prostaglandin‐dependent release of calcitonin gene‐related peptide (CGRP) triggered by endotoxin in rat mesenteric arterial bed

“…Both the constitutive and inducible form of cyclo-oxygenase are found in endothelial cells, fibroblasts and macrophages after treatment with proinflammatory agents, such as endotoxin (Salvemini et al, 1993;Swierkosz et al, 1995). Other studies have shown that NO activates cyclooxygenase in the hypothalamus, leading to corticotrophin-releasing factor release (Karanth et al, 1993). NO increases arachidonic acid-stimulated PGE2 production in fibroblasts (Salvemini et al, 1993).…”

Role of nitric oxide in the control of luteinizing hormone-releasing hormone release in vivo and in vitro.

“…For example, NO appears to mediate via activation of cyclooxygenase the cholinergic and the interleukin-2-induced stimulation of corticotropin-releasing factor release which is mediated by cholinergic neurons within the hypothalamus (22). On the other hand, growth hormone-releasing factor-induced somatostatin release via NO appears to be induced by activation of the guanylate cyclase pathway (23).…”