Alpha-MSH peptides inhibit production of nitric oxide and tumor necrosis factor-alpha by microglial cells activated with beta-amyloid and interferon gamma.
Alpha-melanocyte stimulating hormone (alpha-MSH) is an ancient tridecapeptide with potent inhibitory activity in all major forms of inflammation. The anti-inflammatory message sequence of alpha-MSH resides in the COOH-terminal tripeptide alpha-MSH[11-13]. We tested the influence of alpha-MSH[1-13] and of alpha-MSH[11-13] in a cultured murine microglia cell line known to produce nitric oxide (NO(-)(2)) and tumor necrosis factor (TNFalpha) when stimulated with beta-amyloid protein (Abeta). Melanocortin peptides significantly inhibited release of both NO(-)(2) and TNFalpha into cell-free supernatants from microglia stimulated with Abeta[1-42] or Abeta[25-35] peptides and interferon gamma (IFNgamma). Northern blot analysis demonstrated that alpha-MSH[1-13] and alpha-MSH[11-13] inhibited accumulation of inducible nitric oxide synthase (iNOS) and TNFalpha mRNA was triggered by Abeta stimulation. Abeta/microglial interaction is believed to promote the progression of inflammatory and neurodegenerative changes in senile plaques in Alzheimer's disease. Our data indicate that alpha-MSH peptides might be used to modulate the local response of the brain to Abeta deposition in this neurodegenerative disease.
Galimberti
D
D
Institute of Neurology, Dino Ferrari Center, Milan, 20122, Italy.
Baron
P
P
Meda
L
L
Prat
E
E
Scarpini
E
E
Delgado
R
R
Catania
A
A
Lipton
J M
JM
Scarlato
G
G
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D000521:alpha-MSH / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); D009569:Nitric Oxide; D000521:alpha-MSH; C043156:MSH (11-13); D007371:Interferon-gamma; D009074:Melanocyte-Stimulating Hormones; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse