title: Inhibition of IL-8-mediated MAPK activation in human neutrophils by beta1 integrin ligands.
abstract: Chemokine and integrin receptors must work in concert when circulating leukocytes mobilize toward a site of tissue inflammation or infection. In a previous study, we reported that ligation of the alpha5beta1 integrin with a 120-kDa cell-binding fibronectin fragment (120-kDa FN) in suspensions of human polymorphonuclear leukocytes (PMNLs) inhibited chemotaxis toward the chemokine called interleukin-8 (IL-8). Binding of chemokines to their receptors on leukocytes leads to the activation of heterotrimeric G proteins that initiate multiple signaling cascades, including p38 and p42/p44 mitogen-activated protein kinase (MAPK) pathways. In the present study, we examine the potential interaction of beta1 integrin ligation on chemokine-mediated MAPK signaling in human PMNLs. We demonstrate that blockade of the p42/p44 MAPK signaling pathway by the inhibitor PD98059 suppresses IL-8-mediated PMNL chemotaxis. Furthermore, when PMNLs are pretreated with 120-kDa FN or an activating antibody to beta1 integrins (TS2/16), IL-8-mediated phosphorylation of p42/p44 MAPK is also inhibited. In contrast, pretreating PMNL with a specific ligand (laminin-1) for the alpha6beta1 integrin does not suppress IL-8-mediated phosphorylation of p42/p44 MAPK. These observations demonstrate a desensitization of IL-8-mediated p42/p44 MAPK signaling in response to ligation of the alpha5beta1 integrin in PMNL. Also, they suggest an interplay between integrin and chemokine signaling during PMNL migration through the extracellular matrix.
authors: Center for Cell Biology and Cancer Research, Albany Medical College, NY 12208, USA.
authors: Demetra
authors: D
authors: Xythalis
authors: Mary Beth
authors: MB
authors: Frewin
authors: Paul W
authors: PW
authors: Gudewicz
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D039081:Integrin alpha5beta1 / Q000502:physiology; D039121:Integrin alpha6beta1 / Q000502:physiology; D019012:Integrin beta1 / Q000502:physiology*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007797:Laminin / Q000494:pharmacology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D005353:Fibronectins; D005419:Flavonoids; D007093:Imidazoles; D039081:Integrin alpha5beta1; D039121:Integrin alpha6beta1; D019012:Integrin beta1; D016209:Interleukin-8; D007797:Laminin; D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D011725:Pyridines; D011994:Recombinant Proteins; C121346:laminin 1; C086456:glycyl- arginyl-glycyl-aspartyl-seryl-prolyl-lysine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one