Chen Yabing, Wang Xiaohong, Di Lie, Fu Guoping, Chen Yuhong, Bai Li, Liu Jianzhong, Feng Xu, McDonald Jay M, Michalek Sue, He Yinghong, Yu Mei, Fu Yang-Xin, Wen Renren, Wu Hui, Wang Demin
Department of Pathology, University of Alabama at Birmingham and Veterans Affairs Medical Center, Birmingham, Alabama 35294, USA.
J Biol Chem. 2008 Oct 24;283(43):29593-601. doi: 10.1074/jbc.M802493200. Epub 2008 Aug 26.
Phospholipase Cgamma2 (PLCgamma2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLCgamma2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-kappaB ligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLCgamma2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLCgamma2 markedly diminished RANKL-induced activation of NF-kappaB, AP-1, and NFATc1. Moreover, PLCgamma2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLCgamma2-deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLCgamma2 but not PLCgamma1 restores RANKL-mediated osteoclast differentiation of PLCgamma2-deficient bone marrow-derived monocyte/macrophage. Taken together, PLCgamma2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation.
磷脂酶Cγ2（PLCγ2）是免疫系统中多种受体的重要信号转导效应器。在此我们表明，PLCγ2基因缺陷型小鼠的淋巴结器官发生受损，但脾脏结构和派尔集合淋巴结正常。核因子κB受体激活剂配体（RANKL）是一种肿瘤坏死因子家族细胞因子，对淋巴结器官发生至关重要。重要的是，PLCγ2缺陷严重损害RANKL信号传导，导致RANKL诱导的丝裂原活化蛋白激酶（MAPK）、p38和JNK活化显著减少，但细胞外信号调节激酶（ERK）未受影响。PLCγ2的缺失显著减弱了RANKL诱导的核因子κB（NF-κB）、活化蛋白-1（AP-1）和活化T细胞核因子c1（NFATc1）的活化。此外，PLCγ2缺陷损害了RANKL介导的生物学功能，导致PLCγ2基因缺陷的骨髓巨噬细胞前体在RANKL刺激后无法分化为破骨细胞。重新引入PLCγ2而非PLCγ1可恢复PLCγ2基因缺陷的骨髓来源单核细胞/巨噬细胞的RANKL介导的破骨细胞分化。综上所述，PLCγ2对RANK信号传导至关重要，其缺陷导致淋巴结器官发生缺陷和破骨细胞分化异常。
