Submitted June 2, 2006
Accepted August 12, 2006
IgA Fc receptor I signals apoptosis through the FcR
ITAM and affects tumor growth
Yutaka Kanamaru, Houda Tamouza, Severine Pfirsch, Delphine Elmehdi, Claudine Guerin-Marchand, Marina Pretolani, Ulrich Blank, and Renato C Monteiro*
Institut National de la Sante et de la Recherche Medicale, U699, Bichat Medical School, Paris, FR
Institut National de la Sante et de la Recherche Medicale, U700, Bichat Medical School, Paris, FR
* Corresponding author; email: monteiro{at}bichat.inserm.fr.
The IgA Fc receptor (Fc
RI) has dual pro- and anti-inflammatory functions that are transmitted through the immunoreceptor tyrosine-based activation motifs (ITAM) of the associated FcR
subunit. While the involvement of FcRI in inflammation is well documented, little is known of its anti-inflammatory mechanisms. Here we show that monomeric targeting of FcRI by anti-FcRI Fab or serum IgA triggers apoptosis in human monocytes, monocytic cell lines and FcRI+ transfectants. However, the physiological 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 FcR ITAM, as cells transfected with FcRI or with a chimeric FcRI-FcR responded to death-activating signals, while cells expressing a mutated FcR209L unable to associate with FcR, or an ITAM-mutated chimeric FcRI-FcR, did not respond. FcRI-mediated apoptosis signals were blocked by treatment with the pan-caspase inhibitor zVADfmk, involved proteolysis of procaspase-3, and correlated negatively with SHP-1 concentration. Anti-FcRI Fab treatment of nude mice injected subcutaneously with FcRI+ mast cell transfectants prevented tumor development and halted the growth of established tumors. These findings demonstrate that, upon monomeric targeting, FcRI functions as an FcR ITAM-dependent apoptotic module that may be fundamental for controlling inflammation and tumor growth.
