Inhibition of interleukin-1beta and prostaglandin E(2) thermogenesis by glycyl-glutamine, a pro-opiomelanocortin-derived peptide.
Interleukin-1beta (IL-1beta) and other cytokines produce fever by stimulating prostaglandin E(2) (PGE(2)) synthesis in thermoregulatory regions of the preoptic area and anterior hypothalamus (POA/AH). Prostaglandin E(2) is thought to raise body temperature, at least in part, by stimulating beta-endorphin release from pro-opiomelanocortin neurons that innervate the POA/AH. In this study, we investigated whether glycyl-glutamine (beta-endorphin(30-31)), an inhibitory dipeptide synthesized from beta-endorphin post-translationally, inhibits IL-1beta and PGE(2)-induced hyperthermia. Hyperthermic sites were identified by microinjecting PGE(2) (3 fmol/1 microl) into the medial preoptic area (mPOA) of conscious, unrestrained rats. Interleukin-1beta (1 U) injection into the same PGE(2) responsive thermogenic sites in the mPOA elicited a prolonged rise in colonic temperature (T(c)) (+1.02+/-0.06 degrees C) that persisted for at least 2 h. Glycyl-glutamine (3 nmol) co-injection into the mPOA inhibited IL-1beta thermogenesis completely (T(c)=-0.18+/-0.22 degrees C). Glycyl-glutamine had no effect on body temperature when given alone to normothermic rats. Co-injection of individual amino acids, glycine and glutamine (3 nmol each amino acid), failed to influence IL-1beta-induced thermogenesis, which indicates that Gly-Gln hydrolysis does not explain its inhibitory activity. Glycyl-glutamine (3 nmol) also prevented the rise in body temperature produced by PGE(2) (PGE(2)=0.89+/-0.05 degrees C; PGE(2) plus Gly-Gln=-0.16+/-0.14 degrees C), consistent with evidence that PGE(2) mediates IL-1beta-induced fever. These findings demonstrate that Gly-Gln inhibits the thermogenic response to endogenous pyrogens.
Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, 64108, USA.
G E
GE
Resch
W R
WR
Millington
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000276:immunology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000276:immunology; D004151:Dipeptides / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000276:immunology; D011333:Pro-Opiomelanocortin / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
D004151:Dipeptides; D007375:Interleukin-1; C039788:glycylglutamine; D011333:Pro-Opiomelanocortin; D015232:Dinoprostone