Phospholipase Cγ2 Mediates RANKL-stimulated Lymph Node Organogenesis and Osteoclastogenesis

被引:26
作者
Chen, Yabing [2 ]
Wang, Xiaohong [1 ]
Di, Lie [6 ]
Fu, Guoping [6 ]
Chen, Yuhong [6 ]
Bai, Li [6 ]
Liu, Jianzhong [2 ]
Feng, Xu [2 ]
McDonald, Jay M. [2 ,4 ]
Michalek, Sue [3 ]
He, Yinghong [6 ]
Yu, Mei [6 ]
Fu, Yang-Xin [5 ]
Wen, Renren [6 ]
Wu, Hui [1 ]
Wang, Demin [6 ]
机构
[1] Univ Alabama, Dept Pediat Dent, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA
[3] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA
[4] Vet Affairs Med Ctr, Birmingham, AL 35294 USA
[5] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[6] Blood Ctr SE Wisconsin Inc, Blood Res Inst, Milwaukee, WI 53226 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1074/jbc.M802493200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
Phospholipase C gamma 2 (PLC gamma 2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLC gamma 2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-kappa Bligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLC gamma 2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLC gamma 2 markedly diminished RANKL-induced activation of NF-kappa B, AP-1, and NFATc1. Moreover, PLC gamma 2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLC gamma 2- deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLC gamma 2 but not PLC gamma 1 restores RANKL-mediated osteoclast differentiation of PLC gamma 2- deficient bone marrow-derived monocyte/macrophage. Taken together, PLC gamma 2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation.
引用
收藏
页码:29593 / 29601
页数:9
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