Inhibition of neural and neuroendocrine activity by alpha-interferon: neuroendocrine, electrophysiological, and biochemical studies in the rat.
In our earlier studies we have demonstrated that recombinant human interferon-alpha 2A (rHu-IFN-alpha 2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) secretion following both peripheral and central administration. Furthermore, this effect is antagonized by mu-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. In the present studies, we demonstrate that this effect is also observed with the hybrid recombinant preparation, rHu-IFN-alpha A/D, and a leucocyte-derived rat IFN-alpha preparation. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-alpha 2A (10(3) U), rHu-IFN-alpha A/D (10(4) U), and of Rat-IFN-alpha (1 and 10 U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all three IFN-alpha preparations. No increases in plasma concentrations of corticosterone were observed with doses of rHu-IFN-alpha A/D up to 10(6) U (i.p.) or 7 x 10(5) U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-alpha (10(3) and 5 x 10(3) U). The inhibitory effects of all of the IFN-alpha preparations tested were antagonized by naloxone, but the stimulatory effects of 5 x 10(3) U Rat-IFN-alpha were not. Injections of rHu-IFN-alpha 2A (10(4) U i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus neurons tested, including putative corticotropin-releasing factor-secreting neurons antidromically identified as projecting to the median eminence. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-alpha are mediated by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons. The sensitivity of many central nervous system effects of IFN-alpha to mu-receptor antagonists strongly suggests that the cytokine serves as an endogenous opioid agonist arising from the immune system. In support of this hypothesis we have shown that SH-SY5Y human neuroblastoma cells, differentiated with retinoic acid treatment to express predominantly mu-receptors, are sensitive to rHu-IFN-alpha 2A in vitro. This sensitivity took the form of a dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity. The data yielded an IC50 (95% confidence intervals) value of 7.93 (5.70-11.04) nM for this effect. Neither undifferentiated SH-SY5Y cells nor NG108-15 mouse neuroblastoma x rat glioma hybrid cells (expressing delta-receptors) were affected by rHu-IFN-alpha 2A.(ABSTRACT TRUNCATED AT 400 WORDS)
Saphier
D
D
Department of Pharmacology & Therapeutics, Louisiana State University Medical Center, Shreveport 71130-3932.
Roerig
S C
SC
Ito
C
C
Vlasak
W R
WR
Farrar
G E
GE
Broyles
J E
JE
Welch
J E
JE
D000818:Animals; D003345:Corticosterone / Q000097:blood; D003864:Depression, Chemical; D004594:Electrophysiology; D005910:Glioma; D006801:Humans; D006822:Hybrid Cells; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007370:Interferon Type I; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins; D013045:Species Specificity; D014407:Tumor Cells, Cultured
D007370:Interferon Type I; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C080665:interferon-alpha A-D; D009270:Naloxone; D003345:Corticosterone