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Melanocortin Modulation of Inflammatory Cytokine and Neuroendocrine Responses to Endotoxin in the Monkey

Departments of Medicine and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: sw22{at}columbia.edu.

-MSH has potent antiinflammatory properties, but little is known about the specific melanocortin receptors (MC-Rs) that mediate these effects or about the role of the melanocortin system in modulating cytokine responses to an inflammatory challenge in the primate in vivo. We, therefore, studied the effects of infusion of the -MSH agonist, [Nle⁴,D-Phe⁷]--MSH (NDP-MSH); the -MSH antagonist, SHU9119; and the selective MC3-R agonist, D-Trp8--MSH, compared with saline, on proinflammatory cytokine (TNF-, IL-1ß, and IL-6), antiinflammatory cytokine [IL-10 and IL-1 receptor antagonist (IL-1ra)], and pituitary-adrenal responses to endotoxin in ovariectomized monkeys. In the first study NDP-MSH or SHU9119 was infused iv for 7 h starting at 0800 h, endotoxin was injected at 1000 h, and serial blood samples were collected (n = 6). NDP-MSH significantly attenuated proinflammatory cytokine responses to endotoxin. The area under the response curve (AUC) decreased by 61% for TNF- (P = 0.02), 47% for IL-1ß (P = 0.02), and 41% for IL-6 (P = 0.04); there was no effect on IL-1ra or IL-10. SHU9119 did not affect proinflammatory cytokine responses, but decreased the IL-10 response by 31% (P = 0.03). NDP-MSH also attenuated ACTH (P < 0.001) and cortisol (P = 0.02) responses. In a second study, the effects of D-Trp8--MSH were similarly examined in seven monkeys. The AUC for IL-6 was decreased by 37% (P = 0.04) by D-Trp8--MSH; the AUC for IL-10 was increased by 22%, but this was not significant. However, the ratio of IL-6 to IL-10 was significantly decreased by D-Trp8--MSH (P = 0.04), consistent with a relatively more antiinflammatory cytokine environment. These results indicate that NDP-MSH can attenuate proinflammatory cytokine responses in the primate, consistent with previous studies in the rodent, and provide new evidence for a role for MC3-R in this process. Moreover, they show for the first time that SHU9119, a mixed MC3/4-R antagonist, can decrease the IL-10 response, establishing a physiological role for endogenous MSH in modulating the release of an antiinflammatory cytokine.

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