The molecular basis of IL-21-mediated proliferation

被引:319
作者
Zeng, Rong
Spolski, Rosanne
Casas, Esther
Zhu, Wei
Levy, David E.
Leonard, Warren J.
机构
[1] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA
[2] NYU, Sch Med, Dept Pathol, New York, NY 10003 USA
[3] NYU, Sch Med, Dept Microbiol, New York, NY 10003 USA
关键词
D O I
10.1182/blood-2006-10-054973
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Interleukin-21 (IL-21) is a type I cytokine that modulates functions of T, B, natural killer (NK), and myeloid cells. The IL-21 receptor (IL-21 R) is closely related to the IL-2 receptor beta chain and is capable of transducing signals through its dimerization with the common cytokine receptor gamma chain (gamma(c)), the protein whose expression is defective in humans with X-linked severe combined immunodeficiency. To clarity the molecular basis of IL-21 actions, we investigated the role of tyrosine residues in the IL-21R cytoplasmic domain. Simultaneous mutation of all 6 tyrosines greatly diminished IL-21-mediated proliferation, whereas retention of tyrosine 510 (Y510) allowed full proliferation. Y510 efficiently mediated IL-21-induced phosphorylation of Stat1 and Stat3, but not of Stat5, and CD8(+) T cells from Stat1/Stat3 double knock-out mice exhibited decreased proliferation in response to IL-21 + IL-15. In addition, IL-21 weakly induced phosphorylation of Shc and Akt, and consistent with this, specific inhibitors of the MAPK and PI3K pathways inhibited IL-21-mediated proliferation. Collectively, these data indicate the involvement of the Jak-STAT, MAPK, and PI3K pathways in IL-21 signaling.
引用
收藏
页码:4135 / 4142
页数:8
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