Yamasaki Sho, Ishikawa Eri, Kohno Masayuki, Saito Takashi
Department of Molecular Genetics (H1), Graduate School of Medicine, Chiba University, Chiba, Japan.
Blood. 2004 Apr 15;103(8):3093-101. doi: 10.1182/blood-2003-08-2944. Epub 2003 Dec 11.
Immunoglobulin E (IgE) bound to multivalent antigen (Ag) elicits mast cell degranulation but not survival; on the contrary, IgE in the absence of Ag (IgE(-Ag)) induces survival only but not degranulation. Although these distinct responses are mediated through the same receptor, FcepsilonRI, the molecular mechanism generating the divergence is largely unknown. We recently showed that the signals through FcRgamma chain are essential for IgE(-Ag)-induced mast cell survival as well as IgE(+Ag)-induced degranulation. To determine whether the cellular output is regulated by the quantity of FcRgamma signal, we expressed CD8/FcRgamma chimeras (CD8/gamma) in bone marrow-derived mast cells (BMMCs) from FcRgamma(-/-) mice to manipulate the strength of FcRgamma signals by anti-CD8 cross-linking. Cross-linking of CD8/gamma induced mast cell survival and degranulation. Survival was induced by weaker stimulation than needed for degranulation in terms of anti-CD8 concentration and the valency of chimera. However, sustained extracellular signal-regulated kinase (Erk) activation seems to regulate survival even when the activation signal was strong enough to elicit degranulation. Generation of sustained Erk activation by active mitogen-activated protein kinase kinase (MEK) induced BMMC survival. These results suggest that the duration and the magnitude of FcRgamma signals may determine mast cell survival and degranulation, respectively.
与多价抗原（Ag）结合的免疫球蛋白E（IgE）可引发肥大细胞脱颗粒，但不能使其存活；相反，无抗原情况下的IgE（IgE(-Ag)）仅诱导肥大细胞存活而不引发脱颗粒。尽管这些不同的反应是通过同一受体FcεRI介导的，但产生这种差异的分子机制在很大程度上尚不清楚。我们最近发现，通过FcRγ链传递的信号对于IgE(-Ag)诱导的肥大细胞存活以及IgE(+Ag)诱导的脱颗粒都是必不可少的。为了确定细胞输出是否受FcRγ信号量的调节，我们在来自FcRγ(-/-)小鼠的骨髓来源肥大细胞（BMMC）中表达了CD8/FcRγ嵌合体（CD8/γ），以通过抗CD8交联来操纵FcRγ信号的强度。CD8/γ的交联诱导了肥大细胞的存活和脱颗粒。就抗CD8浓度和嵌合体的价数而言，较弱的刺激即可诱导存活，而脱颗粒则需要更强的刺激。然而，即使激活信号强度足以引发脱颗粒，持续的细胞外信号调节激酶（Erk）激活似乎仍可调节存活。活性丝裂原活化蛋白激酶激酶（MEK）产生的持续Erk激活诱导了BMMC的存活。这些结果表明，FcRγ信号的持续时间和强度可能分别决定肥大细胞的存活和脱颗粒。
