HUMAN MONOCYTE BINDING TO FIBRONECTIN ENHANCES IFN-GAMMA-INDUCED EARLY SIGNALING EVENTS

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 t he onset of inflammatory responses, Moreover, integrin-ligand interact ions trigger signaling pathways that may influence leukocyte phenotype and function at sites of inflammation, In the current studies, we eva luated the combinatorial effects of monocyte adhesion and IFN-gamma on intracellular signaling pathways, IFN-gamma triggers a well-defined s ignal 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 su rfaces, monocytes adherent to fibronectin or RGD exhibited a greater t han threefold increase in steady state levels of IFN-gamma-induced mRN A for the high affinity Fc gamma RI receptor, By electrophoretic mobil ity 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 gamma RI promoter elements, Furthermore, the tyrosine phosphoryl ation of STAT1 and the tyrosine kinases JAK1 and JAK2 was enhanced sig nificantly in RGD-adherent monocytes compared with control cells, Thes e results suggest a novel mechanism by which integrin-mediated cell ad hesion can modulate the magnitude of cytokine-induced signal transduct ion pathways, thereby amplifying cellular events leading to monocyte a ctivation and inflammation.