title: Resolvins Decrease Oxidative Stress Mediated Macrophage and Epithelial Cell Interaction through Decreased Cytokine Secretion.
abstract: BACKGROUND
  Inflammation is a key hallmark of ALI and is mediated through ungoverned cytokine signaling. One such cytokine, interleukin-1beta (IL-1β) has been demonstrated to be the most bioactive cytokine in ALI patients. Macrophages are the key players responsible for IL-1β secretion into the alveolar space. Following the binding of IL-1β to its receptor, "activated" alveolar epithelial cells show enhanced barrier dysfunction, adhesion molecule expression, cytokine secretion, and leukocyte attachment. More importantly, it is an important communication molecule between the macrophage and alveolar epithelium. While the molecular determinants of this inflammatory event have been well documented, endogenous resolution processes that decrease IL-1β secretion and resolve alveolar epithelial cell activation and tissue inflammation have not been well characterized. Lipid mediator Aspirin-Triggered Resolvin D1 (AT-RvD1) has demonstrated potent pro-resolutionary effects in vivo models of lung injury; however, the contribution of the alveoli to the protective benefits of this molecule has not been well documented. In this study, we demonstrate that AT-RvD1 treatment lead to a significant decrease in oxidant induced macrophage IL-1β secretion and production, IL-1β-mediated cytokine secretion, adhesion molecule expression, leukocyte adhesion and inflammatory signaling.
  
  
  METHODS
  THP-1 macrophages were treated with hydrogen peroxide and extracellular ATP in the presence or absence of AT-RvD1 (1000-0.1 nM). A549 alveolar-like epithelial cells were treated with IL-1β (10 ng/mL) in the presence or absence of AT-RvD1 (0.1 μM). Following treatment, cell lysate and cell culture supernatants were collected for Western blot, qPCR and ELISA analysis of pro-inflammatory molecules. Functional consequences of IL-1β induced alveolar epithelial cell and macrophage activation were also measured following treatment with IL-1β ± AT-RvD1.
  
  
  RESULTS
  Results demonstrate that macrophages exposed to H2O2 and ATP in the presence of resolvins show decreased IL-1β production and activity. A549 cells treated with IL-1β in the presence of AT-RvD1 show a reduced level of proinflammatory cytokines IL-6 and IL-8. Further, IL-1β-mediated adhesion molecule expression was also reduced with AT-RvD1 treatment, which was correlated with decreased leukocyte adhesion. AT-RvD1 treatment demonstrated reduced MAP-Kinase signaling. Taken together, our results demonstrate AT-RvD1 treatment reduced IL-1β-mediated alveolar epithelial cell activation. This is a key step in unraveling the protective effects of resolvins, especially AT-RvD1, during injury.
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Ruan
authors: R
authors: Cox
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Oluwakemi
authors: O
authors: Phillips
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Jutaro
authors: J
authors: Fukumoto
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Itsuko
authors: I
authors: Fukumoto
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Prasanna
authors: P
authors: Tamarapu Parthasarathy
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Maria
authors: M
authors: Mandry
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Young
authors: Y
authors: Cho
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Richard
authors: R
authors: Lockey
authors: Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors: Narasaiah
authors: N
authors: Kolliputi
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects*; D011650:Pulmonary Alveoli; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; C518399:resolvin D1; D004281:Docosahexaenoic Acids