TY - JOUR
T1 - The melanocortin agonist AP214 exerts anti-inflammatory and proresolving properties
AU - Montero-Melendez, Trinidad
AU - Patel, Hetal B
AU - Seed, Michael
AU - Nielsen, Søren
AU - Jonassen, Thomas E N
AU - Perretti, Mauro
N1 - Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2011/7
Y1 - 2011/7
N2 - 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 μg/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-1β, tumor necrosis factor-α, and IL-6, respectively. Inhibition of IL-1β 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-1β 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.
AB - 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 μg/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-1β, tumor necrosis factor-α, and IL-6, respectively. Inhibition of IL-1β 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-1β 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.
KW - Animals
KW - Apoptosis
KW - Arthritis, Experimental
KW - Blotting, Western
KW - Cytokines
KW - Disease Models, Animal
KW - Enzyme-Linked Immunosorbent Assay
KW - Humans
KW - Inflammation
KW - Interleukin-1beta
KW - Interleukin-6
KW - Macrophages
KW - Macrophages, Peritoneal
KW - Male
KW - Melanocortins
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mutation
KW - Neutrophils
KW - Peritonitis
KW - Phagocytosis
KW - RNA, Messenger
KW - Receptor, Melanocortin, Type 1
KW - Receptor, Melanocortin, Type 3
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Tumor Necrosis Factor-alpha
KW - alpha-MSH
U2 - 10.1016/j.ajpath.2011.03.042
DO - 10.1016/j.ajpath.2011.03.042
M3 - Journal article
C2 - 21703408
SN - 0002-9440
VL - 179
SP - 259
EP - 269
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -