title: Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress.
abstract: OBJECTIVE
  Myeloperoxidase-enriched monocytes play important roles in inflammatory disease, such as atherosclerosis. We previously demonstrated that α-chlorofatty aldehydes are produced as a result of plasmalogen targeting by myeloperoxidase-derived hypochlorous acid in activated monocytes. Here, we show α-chlorofatty acid (α-ClFA), a stable metabolite of α-chlorofatty aldehydes, accumulates in activated monocytes and mediates the molecular effects of α-ClFA on monocytes/macrophages.
  
  
  RESULTS
  Liquid chromatography-mass spectrometry revealed that α-ClFA is elevated 5-fold in phorbol myristate-stimulated human monocytes rising to ≈20 μmol/L when compared with unstimulated cells. Using human THP-1 monocytes and RAW 264.7 cells as in vitro models, we tested the hypothesis that α-ClFA is a cell death mediator that could potentially participate in pathophysiological roles of monocytes in diseases, such as atherosclerosis. Indeed, 2-chlorohexadecanoic acid, the 16-carbon molecular species of α-ClFA, caused significant apoptosis of primary monocytes. Similarly, 2-chlorohexadecanoic acid also caused apoptosis in THP-1 human monocytes and RAW 264.7 mouse macrophages as determined by annexin V-propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining, respectively. 2-Chlorohexadecanoic acid treatment also increased caspase-3 activity and poly (ADP-ribose) polymerase cleavage in THP-1 cells. 2-Chlorohexadecanoic acid likely elicits apoptosis by increasing both reactive oxygen species production and endoplasmic reticulum stress because antioxidants and CCAAT/enhancer-binding protein homologous protein block such induced cell apoptosis.
  
  
  CONCLUSIONS
  The stable chlorinated lipid, α-ClFA, accumulates in activated primary human monocytes and elicits monocyte apoptosis through increased reactive oxygen species production and endoplasmic reticulum stress, providing a new insight into chlorinated lipids and monocytes in inflammatory disease.
authors.affiliation: From the Edward A. Doisy Department of Biochemistry and Molecular Biology and the Center for Cardiovascular Research, Saint Louis University School of Medicine, MO.
authors.forename: Wen-yi
authors.initials: WY
authors.lastname: Wang
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Albert
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D008401:Gas Chromatography-Mass Spectrometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010169:Palmitic Acids / Q000378:metabolism / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D061251:Primary Cell Culture; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013229:Stearic Acids / Q000378:metabolism / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C532464:2-chlorohexadecanoic acid; C587822:2-chlorooctadecanoic acid; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D010169:Palmitic Acids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013229:Stearic Acids; D051742:Transcription Factor CHOP; D011064:Poly Adenosine Diphosphate Ribose; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D013755:Tetradecanoylphorbol Acetate
keywords: apoptosis; macrophages; monocytes; peroxidase