Central Neurogenic Antiinflammatory Action of α-MSH: Modulation of Peripheral Inflammation Induced by Cytokines and Other Mediators of Inflammation

Abstract

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) has potent antipyretic and antiinflammatory properties. When administered systemically, the naturally occurring molecule and its COOH-terminal tripeptide sequence inhibit inflammation induced by peripherally applied irritants and intradermal injections of mediators of inflammation such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα). We recently found that α-MSH can act solely within the brain to inhibit inflammation caused by a general irritant applied to the skin. This activity appears to be shared with salicylate drugs and the combined observations suggest the existence of descending neurogenic antiinflammatory signals capable of modulating inflammation in peripheral tissues. To improve our knowledge of the scope of this action of the peptide, α-MSH was injected into the cerebral ventricles (i.c.v.) of mice that had received intradermal injections in the ear of mediators of inflammation: IL-1β, IL-8, leukotriene B₄, and platelet-activating factor. The centrally administered peptide inhibited the actions of all of these proinflammatory agents as determined from comparisons with measures of ear edema over time in control animals; this indicates that the central peptide can alter inflammation induced in the periphery by major mediators of inflammation. In tests confined to IL-1β, central administration of α-MSH(11–13) was also effective. These findings support the concept of a descending neurogenic antiinflammatory influence promoted by an action of α-MSH within the brain, an inhibitory influence that is not restricted to modulation of just one or a limited set of the mediators of inflammation.

Effects of Administration of Alpha-Melanocyte Stimulating Hormone (α-MSH) on Some Hematological Values of Alloxan-induced Diabetic Rats

“…The MC-1R, which is capable of binding -MSH with high affinity in humans and rodents, is expressed on immune cells such as monocytes, macrophage cell lines, dendritic cells and neutrophils. Many of the anti-inflammatory indicate that -MSH has a variety of anti-inflammatory activities [35][36][37][38][39][40] . Immunomodulatory activities of -MSH such as suppression of fever induced by IL-1 or IL-6, induction of the anti-inflammatory mediator IL-10, or inhibition of macrophage functions and leukocyte migration are mediated by the activation of this MC-R [41][42][43] .…”

α-MSH Modulates Local and Circulating Tumor Necrosis Factor-α in Experimental Brain Inflammation

“…Central ␣-MSH modulates the increase in circulating TNF-␣ induced by LPS acting solely within the brain Whatever the basis of the increase in circulating TNF-␣, injection of ␣-MSH into the brain reduced it. The dose of ␣-MSH that inhibited circulating TNF-␣ effectively reduced peripheral inflammation after central injection in earlier experiments (Lipton et al, 1991;Ceriani et al, 1994;Macaluso et al, 1994). If circulating TNF-␣ contributes to the inflammatory response in the periphery, central ␣-MSH likely inhibits this inflammation in some part by modulating circulating TNF-␣.…”

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

“…Early studies on anti-inflammatory influences of ␣-MSH (1-13) and (11-13) indicated that these peptides inhibit increases in capillary permeability induced by intradermal injections of histamine or IL-1 in rabbits (Lipton, 1989). Subsequently, anti-inflammatory effects of ␣-MSH peptides were confirmed in acute skin inflammation induced by nonspecific irritants and cytokines Lipton, 1989, 1990;Hiltz et al, 1992;Ceriani et al, 1994b).…”

“…This small peptide shares the anti-inflammatory and antipyretic effects of ␣-MSH (1-13) (Richards and Lipton, 1984b;Hiltz and Lipton, 1989;Mugridge et al, 1991;Hiltz et al, 1992;Poole et al, 1992;Uehara et al, 1992;Watanabe et al, 1993;Ceriani et al, 1994b;Macaluso et al, 1994;Bhardwaj et al, 1996;Ichiyama et al, 1999c;Luger et al, 1999;Haddad et al, 2001;Mandrika et al, 2001). Furthermore, ␣-MSH (11-13) reduced NF-B translocation to the nucleus much as the full-length ␣-MSH Barcellini et al, 2000;Mandrika et al, 2001).…”