Interaction between corticotropin-releasing factor and nitric oxide in mediating the response of the rat hypothalamus to immune and non-immune stimuli.
We sought to determine whether nitric oxide (NO) influences the steady-state gene expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) of the rat hypothalamus and conversely, whether CRF alters the activity of PVN neurons containing NO synthase (NOS), the enzyme responsible for NO formation. Adult male rats exposed to a 30-min session of mild electrofootshocks displayed a significant (P<0.01) increase in mRNA levels of the immediate early gene NGFI-B in the parvocellular portion of the PVN, which contains neurons expressing CRF. This response was decreased (P<0.01) by pretreatment with l-NAME, an arginine derivative that blocks NOS activity. In contrast, the stimulatory effect of interleukin-1beta (IL-1beta), injected intracerebroventricularly (i.c.v.) 45 and 15 min earlier, on NGFI-B mRNA and CRF hnRNA levels, was not. The i.c.v. injection of CRF (1 microg) significantly upregulated transcription of the neuronal isoform of NOS in the PVN, while the ability of i.c.v. IL-1beta to stimulate this signal was not significantly altered by i.c.v. injection of CRF antagonists. These results indicate that even though CRF acts centrally to increase PVN NOS mRNA concentrations, this peptide is not required for the effect of i.c.v. IL-1beta on these transcripts. On the other hand, the ability of shocks to stimulate PVN neuronal activity depends on NO formation. It therefore appears that the functional interactions between NO and CRF-dependent pathways is a function of the type of homeostatic threat to which the organism is exposed.
Lee
S
S
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Rivier
C
C
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D012332:RNA, Heterogeneous Nuclear / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013312:Stress, Physiological / Q000276:immunology / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics; D014667:Vasopressins / Q000494:pharmacology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D014667:Vasopressins; D009569:Nitric Oxide; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester