Systemic α-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release

Abstract

Systemically administered α-melanocyte-stimulating hormone (α-MSH) inhibits endotoxin (lipopolysaccharide; LPS)- or interleukin (IL)-1-induced fever and adrenocortical activation, but the sites of these actions and the mechanisms involved are unknown. The aims of this study were, first, to determine whether melanocortin receptors (MCR) located within the central nervous system mediate the suppressive effects of peripherally administered α-MSH on LPS-induced fever and activation of the pituitary-adrenal axis and, second, to determine whether systemic α-MSH suppresses the LPS-induced rise in plasma IL-6 levels, potentially contributing to its antipyretic effect. Male rats received Escherichia coli LPS (25 μg/kg ip). Core body temperatures (Tb) were determined hourly by radiotelemetry (0–8 h), and blood was withdrawn via venous catheters for plasma hormone immunoassays (0–2 h) and IL-6 bioassay (0–8 h). α-MSH (100 μg/kg ip) completely prevented the onset of LPS-induced fever during the first 3–4 h after LPS and suppressed fever throughout the next 4 h but did not affect Tb in afebrile rats treated with intraperitoneal saline rather than LPS. Intraperitoneal α-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and corticosterone (CS) levels. Intracerebroventricular injection of SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist, completely blocked the antipyretic effect of intraperitoneal α-MSH during the first 4 h after LPS but had no effect on α-MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered α-MSH during the early phase of fever is mediated by MCR within the brain. In contrast, the inhibition of LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal α-MSH appears to be mediated by a different mechanism(s), and these effects do not contribute to its antipyretic action.

The immunomodulating neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages

“…In addition, our research into the immunosuppressive activity of α-MSH and its importance in ocular immune privilege has demonstrated the dynamic contribution of the nervous system to immunoregulation. Further understanding of α-MSH immunomodulating activity will continue to promote the use α-MSH in a therapeutic manner to subdue inflammation and to manipulate immunity to prevent induction of inflammation resulting from specific infections and autoimmune diseases (Casalino-Matsuda et al, 2002;Colombo et al, 2002;Huang et al, 1998;Namba et al, 2002;Nishida et al, 2004;Shiratori et al, 2004). The effects of α-MSH on nitric oxide production by macrophages stimulated by specific TLR.…”

Effects of Acute and Chronic Administration of the Melanocortin Agonist MTII in Mice With Diet-Induced Obesity

“…For this reason, we chose to compare the peripheral versus the central route of administration in these studies. Prior work has revealed that peripherally administered ␣-MSH can activate central processes related to the regulation of fever in rodents (42). In addition, peripheral administration of an MC4 receptor agonist produced substantial weight loss in POMC-deficient mice (15).…”

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

“…The superpotent ␣-MSH analog (Nle 4 ,DPhe 7 )-␣-MSH, was approximately 10 times more potent than ␣-MSH in reducing fever when given centrally . Fevers caused by endotoxin (Martin and Lipton, 1990;Goelst et al, 1991;Villar et al, 1991;Huang et al, 1998) and the cytokines IL-1 (Robertson et al, 1986;Daynes et al, 1987), IL-6 (Martin et al, 1991) and TNF (Martin et al, 1991), but not those caused by IFN-␣ (Hori et al, 1991) and prostaglandin E 2 (Davidson et al, 1992), were inhibited by ␣-MSH. The antipyretic message sequence of ␣-MSH (1-13) resides in the C-terminal tripeptide Lys-Pro-Val (Richards and Lipton, 1984b).…”