Systemically administered alpha-melanocyte-stimulating peptides inhibit NF-kappaB activation in experimental brain inflammation.
The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) and its C-terminal tripeptide alpha-MSH11-13 modulate production of proinflammatory cytokines and inhibit inflammation. We examined whether systemic alpha-MSH and alpha-MSH11-13 inhibit activation of the nuclear transcription factor, nuclear factor kappa B (NF-kappaB), a factor that is essential to expression of proinflammatory cytokines, in experimental murine brain inflammation induced by lipopolysaccharide. Electrophoretic mobility shift assays of nuclear extracts demonstrated that parenteral alpha-MSH inhibited NF-kappaB activation. Western blot analysis revealed that this inhibition was linked to alpha-MSH-induced preservation of expression of IkappaBalpha protein in the brain. The effects of alpha-MSH on NF-kappaB and IkappaBalpha were paralleled by pretreatment with alpha-MSH11-13. Similar effects of the two peptides were observed in mice with nonfunctional melanocortin 1 receptors (MC1R), ruling out the possibility that this receptor subtype is essential to the influence on NF-kappaB. These findings indicate that alpha-MSH peptides given systemically can inhibit NF-kappaB activation induced in acute brain inflammation even in the absence of MC1R.
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9040, USA.
T
T
Ichiyama
T
T
Sakai
A
A
Catania
G S
GS
Barsh
S
S
Furukawa
J M
JM
Lipton
D000818:Animals; D001927:Brain Diseases / Q000139:chemically induced / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009443:Neuritis / Q000139:chemically induced / Q000188:drug therapy*; D000521:alpha-MSH / Q000627:therapeutic use*
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000521:alpha-MSH