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Review Article |
The Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine (N.C., C.N.S.), and Department of Medicine (J.M.D.), Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts; Department of Oral Medicine, Infection, and Immunity (C.N.S.), Harvard School of Dental Medicine, Boston, Massachusetts; Unit for Experimental Asthma and Allergy, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.-E.D.); GlaxoSmithKline, King of Prussia, Pennsylvania (D.W.P.H.); Division of Molecular Pharmacology, Pharmacological Sciences, Milan, Italy (G.E.R.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan (T.S.); Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fu Kuoka, Japan (T.Y.); and Institut National de la Santé et de la Recherche Médicale U698, Hôpital Xavier Bichat secteur Claude Bernard, Paris, France (C.B.)
Abstract
Abstract I. Introduction II. Production of Lipoxins A. Transcellular Biosynthetic Pathways B. Formation of Lipoxin A4 in Animals and in Humans C. Structure-Activity Relationship of Lipoxin A4 III. Molecular Characterization of ALX, the Specific Receptor for Lipoxin A4 A. Identification and Molecular Cloning of Human ALX: Cell Type-Specific Expression B. Murine Homologs of ALX C. Structure-Function Relationship of ALX: Receptor Chimeras for ALX-BLT IV. Flexibility of G Protein-Coupled Ligand-Receptor Interaction: Lipid-versus Peptide-Derived Ligands A. Sequence Homologies and Ligand-Receptor Diversity B. ALX and Structurally Unrelated Peptide Ligands in Vitro C. Emergence of Endogenous Anti-Inflammatory Peptides D. Similarity of Receptor and Ligand Structures in the FPR Family 1. Receptors. 2. Ligands. V. ALX: Historical Perspective and Connection to the FPR A. Discovery of N-Formylated Peptides and the FPR: Why Not Keep the Name FPRL1 for This Receptor? B. What Are the Lines of Evidence and Criteria That Justify This G Protein-Coupled Receptor Being Named ALX? 1. Direct Binding and Signaling with Lipoxin A4: Recombinant Systems. 2. Lipoxin A4 Is the Endogenous Agonist with High Potency. 3. Structure-Activity Relationship in Vitro and in Vivo. VI. ''Aspirin-Triggered'' Lipoxin-Generating Systems A. Transcellular Biosynthesis via Acetylated Cyclooxygenase-2 B. Formation of Aspirin-Triggered Lipoxin in Vivo C. Structure-Activity Relationship of Aspirin-Triggered Lipoxin and Design of Stable Analogs VII. Biological Significance of the Lipoxin-ALX System A. Bioactions of Lipoxin A4 and Aspirin-Triggered Lipoxin A4 in Animal Models of Diseases B. Lipoxin-ALX as a Protective Circuit in Vivo: Lessons from Genetically Engineered Animals 1. ALX and BLT Transgenic Mice. 2. 15-Lipoxygenase Transgenic and Knockout Animals. 3. Counter-Regulatory Role for 5-Lipoxygenase in Lipoxin A4 Biosynthesis. 4. Lipoxin A4 in Other Knockout Mouse Models. VIII. How Does Lipoxin A4 Induce Anti-Inflammatory and Proresolving Signaling? A. Ligand and Receptor Dependence: Direct Functional Links between Lipoxins and ALX 1. Blockade in Vitro. 2. Overexpression in Vitro and in Vivo. 3. Independent Proof. B. In Vitro Cell Type-Specific Anti-Inflammatory Signals 1. Leukocytes: Polymorphonuclear Neutrophils, Monocytes, and Macrophages. 2. Epithelial Cells: Down-Regulation of Proinflammatory Genes. 3. Fibroblast: Inhibition of Proinflammatory Cytokines. C. Leukocyte-Specific Intracellular Signals 1. Distinct ALX-Initiated Cellular Events. a. Polymorphonuclear neutrophils. b. Monocytes. 2. Gene Regulation. IX. Additional Receptors Involved in Lipoxin A4 and Aspirin-Triggered Lipoxin A4 in Vivo Actions A. Cysteinyl-Leukotriene Receptors B. Ah Receptor C. Growth Factor Receptors: Cross-Talk with ALX and/or CysLT1 1. Which of These Molecules Mediate Lipoxin A4 Actions in Vivo? X. Conclusions
Lipoxins (LXs) and aspirin-triggered LX (ATL) are trihydroxytetraene-containing eicosanoids generated from arachidonic acid that are distinct in structure, formation, and function from the many other proinflammatory lipid-derived mediators. These endogenous eicosanoids have now emerged as founding members of the first class of lipid/chemical mediators involved in the resolution of the inflammatory response. Lipoxin A4 (LXA4), ATL, and their metabolic stable analogs elicit cellular responses and regulate leukocyte trafficking in vivo by activating the specific receptor, ALX. ALX was the first receptor cloned and identified as a G protein-coupled receptor (GPCR) for lipoxygenase-derived eicosanoids with demonstrated cell type-specific signaling pathways. ALX at the level of DNA has sequence homology to the N-formylpeptide receptor and as an orphan GPCR was initially referred to as the N-formylpeptide receptor-like 1. Although LXA4 is the endogenous potent ligand for ALX activation, a number of peptides can also activate this receptor to stimulate calcium mobilization and chemotaxis in vitro. In contrast with LXA4, the counterparts of many of these peptides in vivo remain to be established. The purpose of this review is to highlight the molecular characterization of the ALX receptor and provide an overview of the ALX-LXA4 axis responsible for anti-inflammatory and proresolving signals in vivo. The information in this review provides further support for the initial nomenclature proposition for this GPCR as ALX.
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