Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Amino Acid Motifs
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Animals
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Antigens, CD / chemistry
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Antigens, CD / genetics
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Antigens, CD / physiology*
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Apoptosis / physiology*
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Culture Media, Serum-Free
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Cysteine Proteinase Inhibitors / pharmacology
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Enzyme Activation
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Female
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Humans
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Immunoglobulin A / immunology
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Immunoglobulin Fab Fragments / pharmacology
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Inflammation / immunology
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Inflammation / pathology
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Leukemia, Basophilic, Acute / pathology
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Leukemia, Basophilic, Acute / therapy
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Mast Cells / physiology
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Mast Cells / transplantation
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Mice, Transgenic
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Neoplasms / pathology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / physiology
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RNA, Small Interfering / pharmacology
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Rats
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Receptors, Fc / chemistry
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Receptors, Fc / genetics
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Receptors, Fc / physiology*
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Receptors, IgG / physiology
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Recombinant Fusion Proteins / physiology
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Skin Transplantation
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Transfection
Substances
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Amino Acid Chloromethyl Ketones
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Antigens, CD
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Culture Media, Serum-Free
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Cysteine Proteinase Inhibitors
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FCGR1A protein, human
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Fc(alpha) receptor
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Immunoglobulin A
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Immunoglobulin Fab Fragments
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RNA, Small Interfering
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Receptors, Fc
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Receptors, IgG
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Recombinant Fusion Proteins
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, rat
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Caspase 3