title: Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation.
abstract: By generating prostaglandins, cyclooxygenase-2 (Cox-2/Ptgs2) plays a critical role in regulating inflammatory responses. While several inflammatory stimuli have been shown to increase Ptgs2 expression, less is known about how the transcription of this gene is terminated. Here we show that stimulation of macrophages with yeast zymosan, a TLR2/6 and dectin-1 agonist, causes a transient increase in the expression of Ptgs2 accompanied by a simultaneous increase in the expression of the transcriptional repressor, activating transcription factor-3 (Atf3). The expression of Ptgs2 was significantly higher in resident peritoneal macrophages isolated from Atf3(-/-) mice than that from Atf3(+/+) mice and was associated with higher prostaglandin production upon stimulation with zymosan. In activated macrophages, Atf3 accumulated in the nucleus and chromatin-immunoprecipitation analysis showed that Atf3 is recruited to the Ptgs2 promoter region. In acute peritonitis and in cutaneous wounds, there was increased leukocyte accumulation and higher levels of prostaglandins (PGE2/PGD2) in inflammatory exudates of Atf3(-/-) mice compared with WT mice. Collectively, these results demonstrate that during acute inflammation Atf3 negatively regulates Ptgs2 and therefore dysregulation of this axis could potentially contribute to aberrant Ptgs2 expression in chronic inflammatory diseases. Moreover, this axis could be a new therapeutic target for suppressing Ptgs2 expression and the resultant inflammatory responses.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Hellmann
authors.affiliation: Institute of Molecular Cardiology and Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, United States.
authors.forename: Yunan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Institute of Molecular Cardiology and Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210, United States.
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.affiliation: Institute of Molecular Cardiology and Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, United States.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Institute of Molecular Cardiology and Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, United States.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, United States. Electronic address: mspite@partners.org.
authors.forename: Matthew
authors.initials: M
authors.lastname: Spite
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000208:Acute Disease; D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015054:Zymosan / Q000633:toxicity
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D015054:Zymosan; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: Inflammation; Lipid mediators; Prostaglandins