Inhibition of IL-1 beta-induced peripheral inflammation by peripheral and central administration of analogs of the neuropeptide alpha-MSH.
Interleukin-1 (IL-1) is a proinflammatory cytokine, alpha-MSH(1-13) molecules inhibit inflammation induced by cytokines, other mediators of inflammation, and by peripheral irritants. D-valine substitution in the antiinflammatory/antipyretic message sequence [alpha-MSH(11-13), Lys-Pro-Val] of alpha-MSH(1-13) increases the activity of the tripeptide. Our aim was to learn if D-valine substitution also enhances the antiinflammatory activity of the entire alpha-MSH(1-13) molecule and to determine if an antipyretic D-valine-substituted alpha-MSH(8-13) molecule is also antiinflammatory. Intraperitoneal injection of alpha-MSH(1-13) and of (D-Val13)alpha-MSH(1-13) caused dose-related suppression of ear edema induced in mice by intradermal injection of IL-1 beta; the two molecules were equipotent. (D-Val13)alpha-MSH(8-13) likewise inhibited inflammation, but the potency was less than that of the larger molecules. Intracerebroventricular injections of (D-Val13)alpha-MSH(1-13) and of the unsubstituted molecule were equipotent in reducing inflammation; the (D-Val13)alpha-MSH(8-13) molecule was less effective. The results support the idea that the alpha-MSH(1-13) molecule inhibits inflammation and suggest that the L-conformation of alpha-MSH(1-13) is maximally effective with regard to its antiinflammatory activity. The results with alpha-MSH(8-13) are consistent with previous findings of lesser antihost response activity of alpha-MSH fragments that contain the COOH-terminal tripeptide Lys-Pro-Val.
Department of Physiology, Yamaguchi University School of Medicine, Japan.
T
T
Watanabe
M E
ME
Hiltz
A
A
Catania
J M
JM
Lipton
D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D007249:Inflammation; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
D007375:Interleukin-1; D010446:Peptide Fragments; D011994:Recombinant Proteins; C083235:alpha-MSH (8-13), Val(13)-; C083236:alpha-MSH (1-13), Val(13)-; D000521:alpha-MSH