title: 15-Deoxy-Δ12,14-Prostaglandin J2Exerts Proresolving Effects Through Nuclear Factor E2-Related Factor 2-Induced Expression of CD36 and Heme Oxygenase-1.
abstract: OBJECTIVE
  15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) has been shown to rescue cells from inflammatory insults and to participate in the resolution of acute inflammation. In this study, we investigated molecular mechanisms underlying proresolving effects of 15d-PGJ2.
  
  
  RESULTS
  15d-PGJ2injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ2administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ2increased the proportion of macrophages engulfing apoptotic neutrophils, a process called efferocytosis. In addition, when the thioglycollate-elicited mouse peritoneal macrophages were stimulated with 15d-PGJ2, their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ2conducted phagocytic clearance of apoptotic cells to a greater extent than the control cells. Under these conditions, expression of CD36 and heme oxygenase-1 (HO-1) was enhanced along with increased accumulation of the nuclear factor E2-related factor 2 (Nrf2) in the nucleus. Knockdown of Nrf2 abolished 15d-PGJ2-induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ2-induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ2-induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ2, its nonelectrophilic analog 9,10-dihydro-15d-PGJ2lacking the α,β-unsaturated carbonyl group could not induce CD36 expression and efferocytosis.
  
  
  METHODS
  15d-PGJ2, as one of the terminal products of cyclooxygenase-2, exerts proresolving effects through induction of efferocytosis. The results of this study suggest that 15d-PGJ2possesses a therapeutic value in the management of inflammatory disorders.
  
  
  CONCLUSIONS
  15d-PGJ2facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid. Redox Signal. 27, 1412-1431.
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Wonki
authors.initials: W
authors.lastname: Kim
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Lee
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Jang
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Seung Hyeon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Yeon-Hwa
authors.initials: YH
authors.lastname: Lee
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Hahn
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Hoang-Kieu-Chi
authors.initials: HK
authors.lastname: Ngo
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Yeonseo
authors.initials: Y
authors.lastname: Choi
authors.affiliation: 2 School of Biological Sciences, University of Ulsan , Meta-Inflammation Basic Research Laboratory, Ulsan, Republic of Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: 2 School of Biological Sciences, University of Ulsan , Meta-Inflammation Basic Research Laboratory, Ulsan, Republic of Korea.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: 2 School of Biological Sciences, University of Ulsan , Meta-Inflammation Basic Research Laboratory, Ulsan, Republic of Korea.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 3 Department of Pharmacology and Toxicology, College of Medicine, Inha University , Incheon, Republic of Korea.
authors.forename: Young Nam
authors.initials: YN
authors.lastname: Cha
authors.affiliation: 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.|4 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University , Seoul, Republic of Korea.|5 Cancer Research Institute, Seoul National University , Seoul, Republic of Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy*; D010587:Phagocytosis; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D015054:Zymosan / Q000009:adverse effects
chemical_list: C477819:15-deoxyprostaglandin J2; D018955:CD36 Antigens; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015054:Zymosan; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D015230:Prostaglandin D2
keywords: 15-deoxy-Δ12,14-prostaglandin J2; Nrf2; efferocytosis; heme oxygenase-1; resolution of inflammation