IgA Fc receptor I signals apoptosis through the FcRgamma ITAM and affects tumor growth

Blood. 2007 Jan 1;109(1):203-11. doi: 10.1182/blood-2006-06-025882. Epub 2006 Sep 21.


The IgA Fc receptor (FcalphaRI) has dual proinflammatory and anti-inflammatory functions that are transmitted through the immunoreceptor tyrosine-based activation motifs (ITAMs) of the associated FcRgamma subunit. Whereas the involvement of FcalphaRI in inflammation is well documented, little is known of its anti-inflammatory mechanisms. Here we show that monomeric targeting of FcalphaRI by anti-FcalphaRI Fab or serum IgA triggers apoptosis in human monocytes, monocytic cell lines, and FcalphaRI+ 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 FcRgamma ITAM, as cells transfected with FcalphaRI or with a chimeric FcalphaRI-FcRgamma responded to death-activating signals, whereas cells expressing a mutated FcalphaRI(R209L) unable to associate with FcRgamma, or an ITAM-mutated chimeric FcalphaRI-FcRgamma, did not respond. FcalphaRI-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-FcalphaRI Fab treatment of nude mice injected subcutaneously with FcalphaRI+ mast-cell transfectants prevented tumor development and halted the growth of established tumors. These findings demonstrate that, on monomeric targeting, FcalphaRI functions as an FcRgamma ITAM-dependent apoptotic module that may be fundamental for controlling inflammation and tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Amino Acid Motifs
  • Animals
  • Antigens, CD / chemistry
  • Antigens, CD / genetics
  • Antigens, CD / physiology*
  • Apoptosis / physiology*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Culture Media, Serum-Free
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation
  • Female
  • Humans
  • Immunoglobulin A / immunology
  • Immunoglobulin Fab Fragments / pharmacology
  • Inflammation / immunology
  • Inflammation / pathology
  • Leukemia, Basophilic, Acute / pathology
  • Leukemia, Basophilic, Acute / therapy
  • Mast Cells / physiology
  • Mast Cells / transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasms / pathology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / physiology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Receptors, Fc / chemistry
  • Receptors, Fc / genetics
  • Receptors, Fc / physiology*
  • Receptors, IgG / physiology
  • Recombinant Fusion Proteins / physiology
  • Skin Transplantation
  • Transfection


  • Amino Acid Chloromethyl Ketones
  • Antigens, CD
  • Culture Media, Serum-Free
  • Cysteine Proteinase Inhibitors
  • FCGR1A protein, human
  • Fc(alpha) receptor
  • Immunoglobulin A
  • Immunoglobulin Fab Fragments
  • RNA, Small Interfering
  • Receptors, Fc
  • Receptors, IgG
  • Recombinant Fusion Proteins
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, rat
  • Caspase 3