A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcγ Receptors on Macrophages

  • Mary T. Crowley
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Patrick S. Costello
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Cheryl J. Fitzer-Attas
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Martin Turner
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Fanying Meng
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Clifford Lowell
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Victor L. J. Tybulewicz
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
  • Anthony L. DeFranco
    From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom

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<jats:p>Receptors on macrophages for the Fc region of IgG (FcγR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcγR cross-linking. Macrophages derived from Syk-deficient (Syk−) mice were defective in phagocytosis of particles bound by FcγRs, as well as in many FcγR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk− macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk− macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcγRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcγR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcγR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcγR engagement, accompanied by a delay in FcγR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcγR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcγR's analogous to models of signaling by the B and T cell antigen receptors.</jats:p>

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