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

Stephen J. Getting, Linda Gibbs, Adrian J. L. Clark, Roderick J Flower and Mauro Perretti
J Immunol June 15, 1999, 162 (12) 7446-7453;
Stephen J. Getting
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Linda Gibbs
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Adrian J. L. Clark
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Roderick J Flower
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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 μg s.c.) inhibited neutrophil accumulation without altering peripheral blood cell counts or circulating corticosterone levels. A similar effect was seen with α- and β-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.

  • Received November 4, 1998.
  • Accepted April 6, 1999.
  • Copyright © 1999 by The American Association of Immunologists
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The Journal of Immunology: 162 (12)
The Journal of Immunology
Vol. 162, Issue 12
15 Jun 1999
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POMC Gene-Derived Peptides Activate Melanocortin Type 3 Receptor on Murine Macrophages, Suppress Cytokine Release, and Inhibit Neutrophil Migration in Acute Experimental Inflammation
Stephen J. Getting, Linda Gibbs, Adrian J. L. Clark, Roderick J Flower, Mauro Perretti
The Journal of Immunology June 15, 1999, 162 (12) 7446-7453;

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POMC Gene-Derived Peptides Activate Melanocortin Type 3 Receptor on Murine Macrophages, Suppress Cytokine Release, and Inhibit Neutrophil Migration in Acute Experimental Inflammation
Stephen J. Getting, Linda Gibbs, Adrian J. L. Clark, Roderick J Flower, Mauro Perretti
The Journal of Immunology June 15, 1999, 162 (12) 7446-7453;
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