title: Consistent inhibition of cyclooxygenase drives macrophages towards the inflammatory phenotype.
abstract: Macrophages play important roles in defense against infection, as well as in homeostasis maintenance. Thus alterations of macrophage function can have unexpected pathological results. Cyclooxygenase (COX) inhibitors are widely used to relieve pain, but the effects of long-term usage on macrophage function remain to be elucidated. Using bone marrow-derived macrophage culture and long-term COX inhibitor treatments in BALB/c mice and zebrafish, we showed that chronic COX inhibition drives macrophages into an inflammatory state. Macrophages differentiated in the presence of SC-560 (COX-1 inhibitor), NS-398 (COX-2 inhibitor) or indomethacin (COX-1/2 inhibitor) for 7 days produced more TNFα or IL-12p70 with enhanced p65/IκB phosphoylation. YmI and IRF4 expression was reduced significantly, indicative of a more inflammatory phenotype. We further observed that indomethacin or NS-398 delivery accelerated zebrafish death rates during LPS induced sepsis. When COX inhibitors were released over 30 days from an osmotic pump implant in mice, macrophages from peritoneal cavities and adipose tissue produced more TNFα in both the basal state and under LPS stimulation. Consequently, indomethacin-exposed mice showed accelerated systemic inflammation after LPS injection. Our findings suggest that macrophages exhibit a more inflammatory phenotype when COX activities are chronically inhibited.
authors: Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors: Yi Rang
authors: YR
authors: Na
authors: Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors: Yi Na
authors: YN
authors: Yoon
authors: Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors: Dain
authors: D
authors: Son
authors: Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors: Daun
authors: D
authors: Jung
authors: Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors: Gyo Jeong
authors: GJ
authors: Gu
authors: Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors: Seung Hyeok
authors: SH
authors: Seok
mesh_terms: D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015027:Zebrafish
chemical_list: D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D011451:Prostaglandin-Endoperoxide Synthases