The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/1027/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 1027-1039

Articles

A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fc{gamma} Receptors on Macrophages

Mary T. Crowley*, Patrick S. Costello§, Cheryl J. Fitzer-Attas*, Martin Turner§, Fanying Meng{ddagger}, Clifford Lowell{ddagger}, Victor L. J. Tybulewicz§, and Anthony L. DeFranco*

From the G.W. Hooper Foundation, * Department of Microbiology and Immunology, and {ddagger} Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the § National Institute for Medical Research, London NW7 1AA, United Kingdom

Receptors on macrophages for the Fc region of IgG (Fc{gamma}R) 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 Fc{gamma}R cross-linking. Macrophages derived from Syk-deficient (Syk–) mice were defective in phagocytosis of particles bound by Fc{gamma}Rs, as well as in many Fc{gamma}R-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 Fc{gamma}Rs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked Fc{gamma}R-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for Fc{gamma}R-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 Fc{gamma}R engagement, accompanied by a delay in Fc{gamma}R-mediated phagocytosis. These observations demonstrate that Syk is critical for Fc{gamma}R-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 Fc{gamma}R's analogous to models of signaling by the B and T cell antigen receptors.

Address correspondence to Dr. Mary T. Crowley, Scripps Clinic and Research Foundation, 10550 N. Torrey Pines Rd., IMM 25, La Jolla, CA 92037. Phone: 619-784-2195; FAX: 619-784-9180; E-mail: mtcrow{at}scripps.edu

1 Abbreviations used in this paper: AA, arachidonic acid; EA, erythrocytes coated with antibody; Fc{gamma}R, Fc receptor for IgG; GST, glutathione S-transferase; GST–c-Jun, GST fused to the NH2 terminus of c-Jun; ITAM, immunoreceptor tyrosine-based activation motif; JNK, Jun NH2-terminal kinase; LCM, L cell conditioned media; Pl, phosphatidylinositol.


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