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The Journal of Immunology, 1999, 162: 7446-7453.
Copyright © 1999 by The American Association of Immunologists

POMC Gene-Derived Peptides Activate Melanocortin Type 3 Receptor on Murine Macrophages, Suppress Cytokine Release, and Inhibit Neutrophil Migration in Acute Experimental Inflammation1

Stephen J. Getting*, Linda Gibbs*, Adrian J. L. Clark{dagger}, Roderick J Flower* and Mauro Perretti2,*

* William Harvey Research Institute, Charterhouse Square, London, United Kingdom; and {dagger} Chemical Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom

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 µg s.c.) inhibited neutrophil accumulation without altering peripheral blood cell counts or circulating corticosterone levels. A similar effect was seen with {alpha}- and ß-melanocyte stimulating hormones (1–30 µg 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 µM, 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.




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