A role for MC3R in modulating lung inflammation

Getting, Stephen J.; Riffo‐Vasquez, Yanira; Pitchford, Simon; Kaneva, Magdalena; Grieco, Paolo; Page, Clive; Perretti, Mauro; Spina, Domenico

doi:10.1016/j.pupt.2008.09.004

Cited by 58 publications

(62 citation statements)

References 36 publications

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“…Alone, SHU9119 caused a modest inhibition of IL-1 but had no effect on TNF--induced IL-6 or IL-8 production, consistent with its dual agonist/antagonist nature. Remarkably, while SHU9119 was unable to block the effect of -MSH, it abridged the anti-inflammatory activity of D[TRP] 8 --MSH, thus suggesting a potential role for MC 3 in chondroprotection, which agrees with previous studies reporting MC 3 agonist activity of this peptide [51,76,79]. Moreover, at higher concentrations of -MSH, the presence of SHU9119 synergistically reduced IL-6 release, thereby signifying that SHU9119 may be concerting efforts with -MSH via either activation of MC 1 and/or MC 5 .…”

supporting

confidence: 91%

“…reduce cytokine relase is well documented both in vitro [63,64] and in vivo models of inflammation [60][61][62]76], this is the first time their protective properties have been studied in an in situ model of mechanically-induced cartilage injury, and the first indication that targeting the melanocortin receptor system for the development of potential treatment of mechanical/sports injuries and trauma is a viable option.…”

Section: Discussionmentioning

confidence: 91%

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Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Kaneva

Kerrigan

Grieco

et al. 2014

Biochemical Pharmacology

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Conclusion:Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10.Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis.

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supporting

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Kaneva

Kerrigan

Grieco

et al. 2014

Biochemical Pharmacology

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“…It is also expressed in several peripheral tissues, including the placenta, gut, heart, kidney, and peritoneal macrophages ( Chhajlani 1996 ; Gantz et al 1993 ; Getting et al 2003 ; Ni et al 2006 ). Based on its wide distribution, the MC3R has been shown to be involved in regulating cardiovascular function ( Mioni et al 2003 ; Versteeg et al 1998 ), natriuresis ( Chandramohan et al 2009 ; Ni et al 2006 ), and inflammation ( Catania et al 2004 ; Getting et al 2006 ; Getting et al 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Functions of DPLIY motif and helix 8 of human melanocortin-3 receptor

Zhao

Zhili²,

Tao

2015

Journal of Molecular Endocrinology

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The melanocortin-3 receptor (MC3R) is a member of family A G protein-coupled receptors (GPCRs). The MC3R remains the most enigmatic of the melanocortin receptors with regard to its physiological functions, especially the role in energy homeostasis. The N/DPxxY motif and the eighth helix (helix 8) in the carboxyl terminus of GPCRs have been identified to be important for receptor expression, ligand binding, signal transduction and internalization. To gain a better understanding of the structure-function relationship of MC3R, we performed systematic study of all the 20 residues in this domain using alanine-scanning mutagenesis. We showed that although all mutants were expressed normally on cell surface, eleven residues were important for ligand binding and one was indispensable for downstream cAMP generation. F347A showed constitutive activity in cAMP signaling while all the other mutants had normal basal activities. We studied the signaling capacity of nine mutants in the ERK1/2 signaling pathway. All of these mutants showed normal basal ERK1/2 phosphorylation levels. The pERK1/2 levels of six binding- or signaling-defective mutants were enhanced upon agonist stimulation. The unbalanced cAMP and pERK1/2 signaling pathways suggested the existence of biased signaling in MC3R mutants. In summary, we showed that the DPLIY motif and Helix 8 was important for MC3R activation and signal transduction. Our data led to a better understanding of the structure-function relationship of MC3R.

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“…Getting et al reported the anti-inflammatory effects of the analogue D-Trp 8 -␥-MSH in a model of crystal-induced inflammation 7 and, more recently, in an model of allergic inflammation. 8 The same compound was also active in a model of ischemia-reperfusion injury 9 and in inflammatory arthritis. 10 The ␣-MSH-derived C-terminal tripeptide KPV is anti-inflammatory in crystal-induced peritonitis 11 and in two models of inflammatory bowel disease.…”

mentioning

confidence: 99%

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 g/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC 1 , mutant mice but lost in MC 3 null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1␤, tumor necrosis factor-␣, and IL-6, respectively. Inhibition of IL-1␤ release was retained in MC 1 mutant cells but was lost in MC 3 null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC 3 null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo.

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A role for MC3R in modulating lung inflammation

Cited by 58 publications

References 36 publications

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Functions of DPLIY motif and helix 8 of human melanocortin-3 receptor

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

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