Acute phase response to endotoxin: rise in plasma alpha-MSH and effects of alpha-MSH injection

Endotoxins, cell wall components of bacteria, cause a number of biological effects, presumably via induction of potent cytokines. Previous research suggests that the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) and its COOH-terminal tripeptide reduce the effects of cytokines. These molecules evoke antipyretic and anti-inflammatory effects in vivo. Localization of alpha-MSH within lymphocytes and recent observations that alpha-MSH receptors are widespread and that circulating alpha-MSH increases after systemic injection of endogenous pyrogen, a cytokine-containing extract, suggest that the peptide modulates host defense reactions. One aim of the present experiments was to learn whether a rise in circulating alpha-MSH occurs in synchrony with aspects of the acute phase response (APR) in conscious rabbits given endotoxin. A second aim was to learn whether administration of a single large dose of alpha-MSH inhibits all aspects of the APR induced by a low dose of endotoxin. The results indicate that the concentration of circulating alpha-MSH in rabbits does increase along with other changes in the APR (e.g., increase in corticosterone), which suggests that the peptide is widely available to modulate cytokine effects after endotoxin. Contrary to expectations based on previous results, a large dose of the peptide given intravenously inhibited only fever and not other aspects of the APR. The results suggest that the rise in circulating alpha-MSH is an aspect of the APR and that an acute increase in the circulating peptide caused by intravenous injection does not inhibit all other aspects of the host response to endotoxin.