Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance.
Although receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) signaling has been shown to prolong the survival of mature dendritic cells (DCs), the association of RANKL pathway with Fas-mediated apoptosis is obscure. Here, we found that bone marrow-derived DCs (BMDCs) from the Fas-deficient strain MRL/lpr mice, could survive much longer than normal DCs. The expressions of Bcl-x and Bcl-2 and the nuclear transport of NF-kappaB of RANKL-stimulated BMDCs from MRL/lpr mice were significantly up-regulated. By contrast, Fas expression of BMDCs from normal C57BL/6 and MRL(+/+) mice was increased by RANKL stimulation, and an enhanced DC apoptosis was found when stimulated with both RANKL and anti-Fas mAb, which was associated with activation of caspase-3 and caspase-9. Furthermore, the expression of FLIP(L), an inhibitory molecule against Fas-mediated apoptosis, in normal DCs was significantly decreased by RANKL and anti-Fas mAb. Indeed, the adoptive transfer of RANKL-stimulated DCs resulted in rapid acceleration of autoimmunity in MRL/lpr recipients. These findings indicate that the crosstalk between RANKL and Fas signaling in DCs might control immune tolerance.
Izawa
Takashi
T
Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramotocho, Tokushima, Japan.
Ishimaru
Naozumi
N
Moriyama
Keiji
K
Kohashi
Masayuki
M
Arakaki
Rieko
R
Hayashi
Yoshio
Y
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015551:Autoimmunity; D020169:Caspases / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D053245:RANK Ligand; D019014:fas Receptor; D020169:Caspases