Coupling of C3bi to IgG inhibits the tyrosine phosphorylation signaling cascade downstream Syk and reduces cytokine induction in monocytes.
The effect of coupling C3bi to immunoglobulin G (IgG) immune complexes (IC) on their ability to produce protein tyrosine phosphorylation and activation of the mitogen-activated protein kinase (MAPK) and the Akt/protein kinase B (PKB) routes was assessed in human monocytes. Cross-linking Fc receptors for IgG activated the protein tyrosine kinase Syk, phospholipases Cgamma1 and Cgamma2, the MAPK cascade, and the Akt/PKB route. Linkage of C3bi to the gamma-chain of IgG produced a decrease of the protein bands displaying tyrosine phosphorylation, whereas the MAPK cascades and the Akt/PKB route remained almost unaffected. Zymosan particles, which because of their beta-glucan content mimic the effect of fungi, produced a limited increase of tyrosine-phosphorylated protein bands, whereas treatment of zymosan under conditions adequate for C3bi coating increased its ability to induce protein tyrosine phosphorylation. Noteworthy, this was also observed under conditions where other components of serum might be bound by zymosan particles, for instance, serum IgG, thereby suggesting their potential involvement in Syk activation. The induction of cytokines showed a changing pattern consistent with the changes observed in the signaling pathways. IC induced monocyte chemoattractant protein-1 (MCP-1)/CC chemokine ligand 2 (CCL2), interleukin (IL)-1beta, and eotaxin-2/CCL24, which were not observed with C3bi-coated IC. Zymosan induced the expression of tumor necrosis factor alpha (TNF-alpha), TNF-beta, IL-10, IL-6, and MCP-2/CCL8, whereas the cytokine signature of C3bi-coated zymosan also included interferon-inducible protein 10/CXC chemokine ligand 10, platelet-derived growth factor-BB, and I-309/CCL1. Taken together, these findings indicate that C3bi targets the phagocytic cargo, and engagement or diversion of the Syk route determines the phagocyte response.
Trinidad
Antonio García
AG
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas and Universidad de Valladolid, Spain.
de la Puerta
María Luisa
ML
Fernández
Nieves
N
Bayón
Yolanda
Y
Crespo
Mariano Sánchez
MS
Alonso
Andrés
A
D002460:Cell Line; D003179:Complement C3b / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D025461:Feedback, Physiological / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology; D047071:beta-Glucans / Q000494:pharmacology
D016207:Cytokines; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D047071:beta-Glucans; D014443:Tyrosine; D003179:Complement C3b; D015054:Zymosan; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051058:Oncogene Protein v-akt; D051966:Phospholipase C gamma