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.
Ichiyama
T
T
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9040, USA.
Sakai
T
T
Catania
A
A
Barsh
G S
GS
Furukawa
S
S
Lipton
J M
JM
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