| First Author | Montero-Melendez T | Year | 2011 |
| Journal | Am J Pathol | Volume | 179 |
| Issue | 1 | Pages | 259-69 |
| PubMed ID | 21703408 | Mgi Jnum | J:174002 |
| Mgi Id | MGI:5050768 | Doi | 10.1016/j.ajpath.2011.03.042 |
| Citation | Montero-Melendez T, et al. (2011) The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties. Am J Pathol 179(1):259-69 |
| abstractText | 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 mug/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-1beta, tumor necrosis factor-alpha, and IL-6, respectively. Inhibition of IL-1beta 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. Finally, in a model of inflammatory arthritis, AP214 evoked significant reductions in the clinical score. These results indicate that AP214 elicits anti-inflammatory responses, with a preferential effect on IL-1beta release. Furthermore, we describe for the first time a positive modulation of an MC agonist on the process of efferocytosis. In all cases, endogenous MC(3) is the receptor that mediates these novel properties of AP214. These findings might clarify the tissue-protective properties of AP214 in clinical settings and may open further development for novel MC agonists. |
