Blood Journal
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IgA Fc receptor I signals apoptosis through the FcRγ ITAM and affects tumor growth

  1. Yutaka Kanamaru1,3,
  2. Houda Tamouza1,3,
  3. Séverine Pfirsch1,3,
  4. Delphine El Mehdi2,3,
  5. Claudine Guérin-Marchand1,3,
  6. Marina Pretolani2,3,
  7. Ulrich Blank1,3, and
  8. Renato C. Monteiro1,3
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM) U699, Paris, France;
  2. 2Inserm U700, Paris, France; and
  3. 3Université Paris 7-Denis Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France


The IgA Fc receptor (FcαRI) has dual proinflammatory and anti-inflammatory functions that are transmitted through the immunoreceptor tyrosine-based activation motifs (ITAMs) of the associated FcRγ subunit. Whereas the involvement of FcαRI in inflammation is well documented, little is known of its anti-inflammatory mechanisms. Here we show that monomeric targeting of FcαRI by anti-FcαRI Fab or serum IgA triggers apoptosis in human monocytes, monocytic cell lines, and FcαRI+ transfectants. However, the physiologic ligand IgA induced apoptosis only when cells were cultured in low serum conditions, indicating differences with induction of anti-inflammatory signaling. Apoptosis signaling required the FcRγ ITAM, as cells transfected with FcαRI or with a chimeric FcαRI-FcRγ responded to death-activating signals, whereas cells expressing a mutated FcαRIR209L unable to associate with FcRγ, or an ITAM-mutated chimeric FcαRI-FcRγ, did not respond. FcαRI-mediated apoptosis signals were blocked by treatment with the pan-caspase inhibitor zVAD-fmk, involved proteolysis of procaspase-3, and correlated negatively with SHP-1 concentration. Anti-FcαRI Fab treatment of nude mice injected subcutaneously with FcαRI+ mast-cell transfectants prevented tumor development and halted the growth of established tumors. These findings demonstrate that, on monomeric targeting, FcαRI functions as an FcRγ ITAM-dependent apoptotic module that may be fundamental for controlling inflammation and tumor growth.

  • Submitted June 2, 2006.
  • Accepted August 12, 2006.
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