Soluble fibrinogen modulates neutrophil functionality through the activation of an extracellular signal-regulated kinase-dependent pathway.
The integrin family not only mediates the recruitment of polymorphonuclear leukocytes (PMN) to sites of inflammation but also regulates several effector functions by binding to specific ligands. We have recently demonstrated that soluble fibrinogen (sFbg) is able to trigger an activating signal in PMN through an integrin-dependent mechanism. This activation results in degranulation, phagocytosis enhancement, and apoptosis delay. The aim of the present work was to further elucidate the molecular events that follow sFbg interaction with CD11b in human PMN, and the participation of this signaling pathway in the regulation of neutrophil functionality. We demonstrate that sFbg triggers a cascade of intracellular signals that lead to focal adhesion kinase and extracellular signal-regulated kinase 1/2 tyrosine phosphorylation. The activation of this mitogen-activated protein kinase pathway plays a central role in the sFbg modulation of secondary granule degranulation, Ab-dependent phagocytosis, and apoptosis. However, fibrinogen-induced secretory vesicle degranulation occurs independently of the signaling transduction pathways investigated herein. In the context of an inflammatory process, the intracellular signal pathway activated by sFbg may be an early event influencing the functionality of PMN.
Rubel
Carolina
C
División Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina. rubel@sinectis.com.ar
Fernández
Gabriela C
GC
Rosa
Fernanda Alves
FA
Gómez
Sonia
S
Bompadre
Macarena Beigier
MB
Coso
Omar A
OA
Isturiz
Martín A
MA
Palermo
Marina S
MS
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016227:Benzoquinones; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000494:pharmacology / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D047029:Lactams, Macrocyclic; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D012995:Solubility
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D047029:Lactams, Macrocyclic; D011725:Pyridines; D011809:Quinones; D017828:Rifabutin; D019000:Phosphotyrosine; C020754:herbimycin; D005340:Fibrinogen; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one