COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production.
Anorexia and weight loss are frequent complications of acute and chronic infections and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. Selective attenuation of the hypophagic response to infection and maintenance of the production of factors essential for infection control would be a useful addition to antimicrobial therapy in the treatment of human disease. Here, we evaluate the relative contribution of cyclooxygenase (COX)-1- and COX-2-derived prostaglandins to anorexia and weight loss precipitated by systemic immune activation by lipopolysaccharide (LPS). Using COX isoform-selective pharmacological inhibitors and gene knockout mice, we found that COX-2 inhibition during LPS-induced inflammation results in preserved food intake and maintenance of body weight, whereas COX-1 inhibition results in augmented and prolonged weight loss. Regulation of neuropeptide Y, corticotropin-releasing hormone, leptin, and interleukin-6 does not change as a function of COX-2 inhibition after LPS administration. Our data implicate COX-2 inhibition as a therapeutic target to maintain nutritional status while still allowing a normal cytokine response during infection.
Johnson
Paulette M
PM
Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Vogt
Sherri K
SK
Burney
Mary W
MW
Muglia
Louis J
LJ
D000818:Animals; D000855:Anorexia / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D002149:Energy Intake; D004734:Energy Metabolism; D007031:Hypothalamus / Q000737:chemistry; D007109:Immunity; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000276:immunology*; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology; D015431:Weight Loss; D000096926:Benzenesulfonamides
D003346:Corticotropin-Releasing Hormone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009478:Neuropeptide Y; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C115461:SC 560; C496512:Ptgs1 protein, mouse