IgA Fc receptor I signals apoptosis through the FcRgamma ITAM and affects tumor growth.
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.
Kanamaru
Yutaka
Y
Institut National de la Santé et de la Recherche Médicale (INSERM) U699, Paris, France.
Tamouza
Houda
H
Pfirsch
Séverine
S
El-Mehdi
Delphine
D
Guérin-Marchand
Claudine
C
Pretolani
Marina
M
Blank
Ulrich
U
Monteiro
Renato C
RC
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015471:Leukemia, Basophilic, Acute / Q000473:pathology / Q000628:therapy; D008407:Mast Cells / Q000502:physiology / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000473:pathology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016038:Skin Transplantation; D014162:Transfection
D000590:Amino Acid Chloromethyl Ketones; D015703:Antigens, CD; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; C489017:FCGR1A protein, human; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D007140:Immunoglobulin Fab Fragments; D034741:RNA, Small Interfering; D011961:Receptors, Fc; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509250:Ptpn6 protein, rat; D053148:Caspase 3