title: CCL3 (MIP-1alpha) induces in vitro migration of GM-CSF-primed human neutrophils via CCR5-dependent activation of ERK 1/2.
abstract: CCL3 (MIP-1alpha), a prototype of CC chemokines, is a potent chemoattractant toward human neutrophils pre-treated with GM-CSF for 15 min. GM-CSF-treated neutrophils migrate also to the selective CCR5 agonist CCL4 (MIP-1beta). CCL3- and CCL4-triggered migration of GM-CSF-primed neutrophils was inhibited by the CCR5 antagonist TAK-779. Accordingly, freshly isolated neutrophils express CCR5. Extracellular signal-regulated kinases (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) inhibitors blocked CCL3-induced migration of GM-CSF-primed neutrophils. When the activation of ERK-1/2 and p38 MAPK by CCL3 and the classical neutrophilic chemokine CXCL8 (IL-8) were compared, both the chemokines were capable of activating p38 MAPK. On the contrary, whereas both ERK-1 and ERK-2 were activated by CXCL8, no ERK-1 band was detectable after CCL3 triggering. Finally, neutrophil pre-treatment with GM-CSF activated both ERK-1 and ERK-2. This suggests that by activating ERK-1, GM-CSF renders neutrophils rapidly responsive to CCL3 stimulation throughout CCR5 which is constitutively expressed on the cell surface.
authors.affiliation: Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, G. Gaslini Institute, Genoa, Italy. otto@unige.it
authors.forename: Luciano
authors.initials: L
authors.lastname: Ottonello
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Arduino
authors.forename: Marina
authors.initials: M
authors.lastname: Mancini
authors.forename: Anna
authors.initials: A
authors.lastname: Corcione
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
mesh_terms: D000577:Amides / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D002462:Cell Membrane / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D011518:Proto-Oncogene Proteins; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C119369:TAK 779; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases