Submitted November 29, 2006
Accepted March 8, 2007
Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance
Takashi Izawa, Naozumi Ishimaru, Keiji Moriyama, Masayuki Kohashi, Rieko Arakaki, and Yoshio Hayashi*
Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
* Corresponding author; email: hayashi{at}dent.tokushima-u.ac.jp.
Although receptor activator of nuclear factor (NF)-
B 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-B of RANKL-stimulated BMDCs from MRL/lpr mice were significantly upregulated. 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 FLIPL, 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.
