ALPHA-MELANOCYTE-STIMULATING HORMONE REDUCES ENDOTOXIN-INDUCED LIVER INFLAMMATION

alpha-Melanocyte-stimulating hormone (MSH) is a potent antiinflammator y agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation, We showed pre viously that alpha-MSH inhibits nitric oxide (NO) production in cultur ed macrophages, To determine how alpha-MSH acts in vivo, we induced ac ute hepatic inflammation by administering endotoxin (LPS) to mice pret reated with Corynebacterium parvum. alpha-MSH prevented liver inflamma tion even when given 30 min after LPS administration, To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, inf iltrating inflammatory cells, cytokines, and chemokines. alpha-MSH inh ibited systemic NO production, hepatic neutrophil infiltration, and in creased hepatic mRNA abundance for TNF alpha, and the neutrophil and m onocyte chemokines (KC/IL-8 and MCP-I). We conclude that alpha-MSH pre vents LPS-induced hepatic inflammation by inhibiting production of che moattractant chemokines which then modulate infiltration of inflammato ry cells, Thus, alpha-MSH has an effect very early in the inflammatory cascade.