Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis
Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis
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DOI：
10.1182/blood-2006-08-040352
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发表时间：
2007-03-15
期刊：
影响因子：
20.3
通讯作者：
Ernst, Matthias
中科院分区：
文献类型：
--
作者：
Jenkins, Brendan J.;Roberts, Andrew W.;Ernst, Matthias
我们先前已经证明，在gp130(Y757F/Y757F)小鼠中，通过白介素6(IL-6)细胞因子家族受体gp130的STAT3过度激活会导致许多造血和淋巴病变，包括中性粒细胞增多、血小板增多、脾肿大和淋巴结病。因为IL-6和IL-11都是通过gp130同源二聚体发出信号的，所以我们在这里报告了一种遗传学方法来剖析它们在这些病理过程中各自的作用。在缺乏IL-6(9P130(Y757F1Y757F)：1L-6(-/-))或IL-11受体α亚单位(gp130(Y757F/Y757F)：IL-11Rα1(-/-))的9P130(Y757FN757F)小鼠中，没有中性粒细胞和血小板增多症，这与正常的骨髓室有关。9P130(Y757F/Y757F)小鼠骨髓造血祖细胞和巨核细胞的增加可归因于IL-6或IL-11在STAT3诱导的转化生长因子-β信号的损伤中的增加，转化生长因子-β信号是这些系的抑制因子。相反，IL-6的缺失，而不是IL-11信号的缺失，阻止了gp130(Y717F1Y757F)小鼠脾肿大、异常淋巴细胞生成和淋巴器官中STAT3的过度激活。此外，淋巴器官中STAT3的过度激活与IL-6Rα的表达增加有关，而在9P130(Y757F/Y757F)：STAT3(+/-)活性正常的9P130(Y757F/Y757F)小鼠中，IL-6Rα的表达减少。总的来说，这些数据在基因上定义了IL-6和IL-11在驱动STAT3过度激活所介导的病理造血和淋巴反应中的不同作用。
We have previously demonstrated that STAT3 hyperactivation via the interleukin 6 (IL-6) cytokine family receptor gp130 in gP130(Y757F/Y757F) mice leads to numerous hematopoietic and lymphoid pathologies, including neutrophilia, thrombocytosis, splenomegaly, and lymphadenopathy. Because IL-6 and IL-11 both signal via a gp130 homodimer, we report here a genetic approach to dissect their individual roles in these pathologies. Neutrophilia and thrombocytosis were absent in 9P130(Y757FN757F) mice lacking either IL-6 (9P130(Y757F1Y757F):1L-6(-/-)) or the IL-11 receptor a subunit (gp130(Y757F/Y757F) :IL-11R alpha 1(-/-)), and this was associated with a normalized bone marrow compartment. The elevated myelopoiesis and megakaryopoiesis in bone marrow of 9P130(Y757F/Y757F) mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor beta (TGF-beta) signaling, which is a suppressor of these lineages. in contrast, the absence of IL-6, but not IL-11 signaling, prevented the splenomegaly, abnormal lymphopoiesis, and STAT3 hyperactivation in lymphoid organs of gp130(Y717F1Y757F) mice. Furthermore, hyperactivation of STAT3 in lymphoid organs was associated with increased expression of IL-6R alpha, and lL-6R alpha expression was reduced in 9P130(Y757F/Y757F):Stat3(+/-) mice displaying normal levels of STAT3 activity. Collectively, these data genetically define distinct roles of IL-6 and IL-11 in driving pathologic hematopoietic and lymphoid responses mediated by STAT3 hyperactivation.