Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3.

Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3.
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DOI:
10.1016/j.cellimm.2011.01.008
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发表时间:
2011
影响因子:
4.3
通讯作者:
Mapara, Markus Y.
Mapara, Markus Y.
中科院分区:
医学4区
文献类型:
--
作者:
Ma, Hui-Hui;Ziegler, Judy;Li, Cuiling;Sepulveda, Antonia;Bedeir, Ahmed;Grandis, Jennifer;Lentzsch, Suzanne;Mapara, Markus Y.

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本研究的目的是描述完全主要组织相容性(MHC)-错配异体骨髓移植(BMT)后GVHD发展过程中STAT1和STAT3激活的时间和空间序列。通过western blotting、phospho-flow cytometry和electromobility shift assay (EMSA)评估GVHD靶器官中炎症信号通路的激活情况。GVHD的发生与表达CD4+ T细胞和CD8+T细胞的phospho[p]-STAT1和p- stat3显著扩增相关。gvhd特异性STAT3/STAT1的激活先于核因子-κB (NF-κB)和丝裂原活化蛋白激酶(MAPK)的激活,并与随后诱导STAT1或STAT3依赖性炎症基因表达程序(如IRF-1、SOCS1、IL-17的表达)相关。我们的研究可能有助于建立导致GVHD发展的信号事件的功能层次结构,并可能有助于设计新的GVHD分子靶向治疗方法。
The aim of this study was to delineate the temporal and spatial sequence of STAT1 and STAT3 activation during development of GVHD following fully Major Histocompatibility (MHC)-mismatched allogeneic Bone Marrow Transplantation (BMT). Activation of inflammatory signaling pathways in GVHD target organs was assessed by western blotting, phospho-flow cytometry and electromobility shift assays (EMSA). Development of GVHD was associated with significant expansion of phospho[p]-STAT1 and p-STAT3 expressing CD4+ T cells and CD8+T cells. GVHD-specific STAT3/STAT1 activation preceded activation of Nuclear Factor-κB (NF-κB) and Mitogen Activated Protein Kinase (MAPK) and was associated with subsequent induction of STAT1 or STAT3-dependent inflammatory gene expression programs (e.g. expression of IRF-1, SOCS1, IL-17). Our studies may help to establish a functional hierarchy of the signaling events leading to the development of GVHD and could be helpful in designing new molecularly targeted treatment approaches for GVHD.
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