title: Human monocyte binding to fibronectin enhances IFN-gamma-induced early signaling events.
abstract: Leukocyte integrins are fundamentally important in modulating adhesion to extracellular matrix components and to other cells. This integrin-mediated adhesion controls leukocyte arrest and extravasation during the onset of inflammatory responses. Moreover, integrin-ligand interactions trigger signaling pathways that may influence leukocyte phenotype and function at sites of inflammation. In the current studies, we evaluated the combinatorial effects of monocyte adhesion and IFN-gamma on intracellular signaling pathways. IFN-gamma triggers a well-defined signal transduction pathway, which although not directly stimulated by monocyte adherence to fibronectin or arginine-glycine-aspartate (RGD)-coated substrata, was enhanced significantly in these matrix-adherent cells. Compared with monocytes in suspension or adherent on plastic surfaces, monocytes adherent to fibronectin or RGD exhibited a greater than threefold increase in steady state levels of IFN-gamma-induced mRNA for the high affinity Fc gammaRI receptor. By electrophoretic mobility shift assays, this increase in mRNA was associated with a 5- to 10-fold increase in the STAT1-containing DNA-binding complex that binds to Fc gammaRI promoter elements. Furthermore, the tyrosine phosphorylation of STAT1 and the tyrosine kinases JAK1 and JAK2 was enhanced significantly in RGD-adherent monocytes compared with control cells. These results suggest a novel mechanism by which integrin-mediated cell adhesion can modulate the magnitude of cytokine-induced signal transduction pathways, thereby amplifying cellular events leading to monocyte activation and inflammation.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: McCarthy
authors.forename: B V
authors.initials: BV
authors.lastname: Vachhani
authors.forename: S M
authors.initials: SM
authors.lastname: Wahl
authors.forename: D S
authors.initials: DS
authors.lastname: Finbloom
authors.forename: G M
authors.initials: GM
authors.lastname: Feldman
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D002448:Cell Adhesion; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D039441:Integrin alpha4; D039482:Integrin alpha5; D007371:Interferon-gamma / Q000502:physiology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D009000:Monocytes / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG / Q000096:biosynthesis* / Q000235:genetics; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D005353:Fibronectins; D039482:Integrin alpha5; D009842:Oligopeptides; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D039441:Integrin alpha4; C047981:arginyl-glycyl-aspartic acid; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2