THE GENERATION OF NITRIC-OXIDE AND CARBON-MONOXIDE PRODUCES OPPOSITE EFFECTS ON THE RELEASE OF IMMUNOREACTIVE INTERLEUKIN-1-BETA FROM THE RAT HYPOTHALAMUS IN-VITRO - EVIDENCE FOR THE INVOLVEMENT OF DIFFERENT SIGNALING PATHWAYS

Both the cytokine, interleukin-1 (IL-1), and the gaseous neurotransmit ters, nitric oxide (NO) and carbon monoxide (GO), have been implicated in the control of neuroendocrine functions, such as the release of CR H and luteotropic hormone-releasing hormone from the hypothalamus. Tho ugh increased levels of IL-1 in this brain region are unambiguously as sociated with enhanced CRH and reduced luteotropic hormone-releasing h ormone release, the net effects of the two gases are still unclear, bu t in vivo and in vitro evidence suggests that the generation of NO and CO within the hypothalamus might counteract the stimulatory effects o f IL-1 and bacterial lipopolysac-charide on the neuroendocrine stress axis. In this study, we have investigated the effects of NO and CO on the release of immunoreactive (ir)-IL-1 beta from the rat hypothalamus in vitro. It was observed that the NO donor, sodium nitroprusside (SN P), stimulates ir-IL-1 beta release under basal conditions, precursor through the heme oxygenase pathway, has no effect on basal ir-IL-1 bet a release but inhibits release stimulated by high K+ concentrations. T he opposite effects of the two gases on cytokine release seemed to be caused by the activation of different signaling pathways, because: 1) SNP, but not GO-saturated solutions, is able to increase cyclic GMP le vels in hypothalamic tissue; 2) GO-saturated solutions increase PGE2 p roduction and release from the hypothalamic explants, whereas SNP has no effect; 3) SNP-stimulated ir-IL-1 beta release is counteracted by a selective inhibitor of soluble guanylyl cyclase, LY 83583, but not by a cyclooxygenase inhibitor, indomethacin; and 4) conversely, indometh acin, but not LY 83583, reverses the inhibitory effect of hemin on K+- stimulated ir-IL-1 beta release. It is concluded that NO and CO signal in the rat hypothalamus via the activation of soluble guanylyl cyclas e and cyclooxygenase, respectively.