title: TNF-alpha promotes LPA1- and LPA3-mediated recruitment of leukocytes in vivo through CXCR2 ligand chemokines.
abstract: Lysophosphatidic acid (LPA) is a bioactive lysophospholipid present in low concentrations in serum and biological fluids but in high concentrations at sites of inflammation. LPA evokes a variety of cellular responses via binding to and activation of its specific G protein-coupled receptors (GPCR), namely LPA(1-6). Even though LPA is a chemoattractant for inflammatory cells in vitro, such a role for LPA in vivo remains largely unexplored. In the present study, we used the murine air pouch model to study LPA-mediated leukocyte recruitment in vivo using selective LPA receptor agonist/antagonist and LPA(3)-deficient mice. We report that 1) LPA injection into the air pouch induced leukocyte recruitment and that both LPA(1) and LPA(3) were involved in this process; 2) LPA stimulated the release of the pro-inflammatory chemokines keratinocyte-derived chemokine (KC) and interferon-inducible protein-10 (IP-10) in the air pouch; 3) tumor necrosis factor-α (TNF-α) injected into the air pouch prior to LPA strongly potentiated LPA-mediated secretion of cytokines/chemokines, including KC, IL-6, and IP-10, which preceded the enhanced leukocyte influx; and 4) blocking CXCR2 significantly reduced leukocyte infiltration. We suggest that LPA, via LPA(1) and LPA(3) receptors, may play a significant role in inducing and/or sustaining the massive infiltration of leukocytes during inflammation.
authors.affiliation: Rheumatology and Immunology Research Center, CHUQ-CHUL Research Center and Faculty of Medicine, Laval University, Québec City, Québec, Canada.
authors.forename: Chenqi
authors.initials: C
authors.lastname: Zhao
authors.forename: Anne
authors.initials: A
authors.lastname: Sardella
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Patrice E
authors.initials: PE
authors.lastname: Poubelle
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Fernandes
authors.forename: Sylvain G
authors.initials: SG
authors.lastname: Bourgoin
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D055786:Gene Knockout Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D063086:Organothiophosphates / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C473891:1-oleoyl-2-O-methyl-rac-glycerophosphothionate; D018925:Chemokines; D008024:Ligands; D008246:Lysophospholipids; D063086:Organothiophosphates; D010712:Phosphatidic Acids; D023063:Receptors, Interleukin-8B; D049368:Receptors, Lysophosphatidic Acid; D014409:Tumor Necrosis Factor-alpha; C032881:lysophosphatidic acid