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Project TitleModulation of Cytokine Induced Gene Expression
Principal InvestigatorG. M. Feldman
LaboratoryLaboratory of Immunobiology; Division of Monoclonal Antibodies; Office of Therapeutics Research and Review
Project SummaryLeukocyte 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 which may influence leukocyte phenotype and function at sites of inflammation. In the current studies, we evaluated the combinatorial effects of monocyte adhesion and IFNg on intracellular signaling pathways. IFNg triggers a well defined signal transduction pathway, which although not directly stimulated by monocyte adherence to fibronectin-(FN) or arginine-glycine-aspartate (RGD)-coated substrata, was significantly enhanced in these matrix-adherent cells. Compared to monocytes in suspension or adherent on plastic surfaces, monocytes adherent to FN or RGD exhibited a greater than 3 fold increase in steady state levels of IFNg-induced messenger RNA for the high affinity FcgRI receptor. By electrophoretic mobility shift assays, this increase in mRNA was associated with a 5-10 fold increase in the Stat1-containing DNA binding complex that binds to FcgRI promoter elements. Furthermore, the tyrosine phosphorylation of Stat1 and the tyrosine kinases JAK1 and JAK2 was significantly enhanced in RGD-adherent monocytes compared to 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.
Last Updated: 4/1/2002
Date created: September 25, 2003 |
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