Inhibition of interleukin-l beta and prostaglandin E-2 thermogenesis by glycyl-glutamine, a pro-opiomelanocortin-derived peptide

Interleukin-1 beta (IL-1 beta) and other cytokines produce fever by stimula ting prostaglandin E-2 (PGE(2)) synthesis in thermoregulatory regions of th e preoptic area and anterior hypothalamus (POA/AH). Prostaglandin E-2 is th ought to raise body temperature, at least in part, by stimulating beta -end orphin release from pro-opiomelanocortin neurons that innervate the POA/AK. In this study, we investigated whether glycyl-glutamine (beta -endorphin(3 0-31)), an inhibitory dipeptide synthesized from beta -endorphin post-trans lationally, inhibits IL-1 beta and PGE(2)-induced hyperthermia. Hyperthermi c sites were identified by microinjecting PGE(2) (3 fmol/1 mul) into the me dial preoptic area (mPOA) of conscious, unrestrained rats. Interleukin-1 mu beta (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 degreesC) that persisted for at least 2 h. Glycyl-glutamine (3 nmol) co- injection into the mPOA inhibited IL-1 beta thermogenesis completely (T-c=- 0.18+/-0.22 degreesC). Glycyl-glutamine had no effect on body temperature w hen given alone to normothermic rats. Co-injection of individual amino acid s, glycine and glutamine (3 nmol each amino acid), failed to influence IL-1 beta -induced thermogenesis, which indicates that Gly-Gln hydrolysis does not explain its inhibitory activity. Glycyl-glutamine (3 nmol) also prevent ed the rise in body temperature produced by PGE(2) (PGE(2)=0.89+/-0.05 degr eesC; PGE(2) plus Gly-Gln=-0.16+/-0.14 degreesC), consistent with evidence that PGE(2) mediates IL-1 beta -induced fever. These findings demonstrate t hat Gly-Gln inhibits the thermogenic response to endogenous pyrogens. (C) 2 001 Elsevier Science B.V. All rights reserved.