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Originally published online as doi:10.1189/jlb.0602319 on May 22, 2003

Published online before print May 22, 2003
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(Journal of Leukocyte Biology. 2003;73:802-814.)
© 2003 by Society for Leukocyte Biology

Activation of CR3-mediated phagocytosis by MSP requires the RON receptor, tyrosine kinase activity, phosphatidylinositol 3-kinase, and protein kinase C {zeta}

Michael A. Lutz and Pamela H. Correll

Department of Veterinary Science, Pennsylvania State University, Pathobiology Graduate Program, University Park

Correspondence: Dr. Pamela Correll, Department of Veterinary Science, 115 Henning Building, Pennsylvania State University, University Park, PA 16802. E-mail: phc7{at}psu.edu

Macrophage-stimulating protein (MSP) promotes the phagocytosis of C3bi-coated erythrocytes by resident peritoneal macrophages, although the mechanism by which this occurs is largely unknown. We show that MSP-induced complement-mediated phagocytosis requires the RON receptor tyrosine kinase and the {alpha}Mß2 integrin, as evidenced by the inability of RON-/- and {alpha}M-/- peritoneal macrophages to augment phagocytosis of complement-coated sheep erythrocytes in response to MSP. MSP stimulation of macrophages results in tyrosine phosphorylation and AKT activation, and inhibitor studies demonstrate a phagocytic requirement for tyrosine kinase and phosphatidylinositol 3-kinase (PI-3K) activity as well as activity of the atypical protein kinase C (PKC) isoform {zeta}, which localizes to MSP-induced phagosomes containing complement-coated beads. Additionally, MSP augments the ability of peritoneal macrophages to bind to intercellular adhesion molecule-1 (ICAM-1) via the {alpha}Mß2 integrin. MSP-induced ICAM-1 adhesion is also dependent on tyrosine kinase activity, PI-3K, and PKC {zeta}, indicating that these signaling requirements are upstream of complement receptor 3 activation.

Key Words: macrophage-stimulating protein • complement receptor 3 • intercellular adhesion molecule-1




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