title: POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation.
abstract: To investigate the relevance of adrenocorticotrophic hormone (ACTH) therapy in human gouty arthritis, we have tested the effect of several ACTH-related peptides in a murine model of experimental gout. Systemic treatment of mice with ACTH4-10 (MEHFRWG) (10-200 microgram s. c.) inhibited neutrophil accumulation without altering peripheral blood cell counts or circulating corticosterone levels. A similar effect was seen with alpha- and beta-melanocyte stimulating hormones (1-30 microgram s.c.). In vivo release of the chemokine KC-(detected in the lavage fluids before maximal influx of neutrophils) was significantly reduced (-50 to -60%) by ACTH4-10. Macrophage activation in vitro, determined as phagocytosis and KC release, was inhibited by ACTH and ACTH4-10 with approximate IC50 values of 30 nM and 100 microM, respectively. The melanocortin receptor type 3/4 antagonist SHU9119 prevented the inhibitory actions of ACTH4-10 both in vitro and in vivo. However, melanocortin type 3, but not type 4, receptor mRNA was detected in mouse peritoneal macrophages by RT-PCR. Therefore, we propose that activation of this receptor type by ACTH4-10 and related amino acid sequences attenuates KC release (and possibly production of other cytokines) from macrophages with consequent inhibition of the host inflammatory response, thus providing a notional anti-inflammatory mechanism for ACTH that is unrelated to stimulation of glucocorticoid release.
authors.affiliation: William Harvey Research Institute, London, United Kingdom.
authors.forename: S J
authors.initials: SJ
authors.lastname: Getting
authors.forename: L
authors.initials: L
authors.lastname: Gibbs
authors.forename: A J
authors.initials: AJ
authors.lastname: Clark
authors.forename: R J
authors.initials: RJ
authors.lastname: Flower
authors.forename: M
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000208:Acute Disease; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D015210:Arthritis, Gouty / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D002464:Cell Migration Inhibition; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; C011394:ACTH (4-10)