Heme mediated STAT3 activation in severe malaria.
Heme mediated STAT3 activation in severe malaria.
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DOI：
10.1371/journal.pone.0034280
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Stiles JK
中科院分区：
文献类型：
--
作者：
Liu M;Amodu AS;Pitts S;Patrickson J;Hibbert JM;Battle M;Ofori-Acquah SF;Stiles JK
尽管有足够的治疗方法，但严重疟疾[脑疟疾（CM）、严重疟疾贫血（SMA）、急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）]的死亡率仍然很高。我们实验室和其他实验室最近的研究揭示了趋化因子 CXCL10/CXCR3、Heme/HO-1 和 STAT3 与脑型疟疾严重程度和死亡率之间迄今未知的相关性。尽管 Heme/HO-1 和 CXCL10/CXCR3 相互作用直接参与 CM 和致命性疾病的发病机制，但决定 Heme/HO-1 和 CXCL10/CXCR3 在这些条件下如何表达和调节的机制仍不清楚。因此，我们测试了以下假设：这些因素共享共同的信号传导途径并且可能相互调节。我们首先利用成熟的实验性脑型疟疾小鼠（ECM、伯氏疟原虫 ANKA）模型阐明了 Heme/HO-1、CXCL10/CXCR3 和 STAT3 在 CM 发病机制中的作用。然后，我们在小鼠内皮细胞系CRL-2581中进一步确定了STAT3调节HO-1和CXCL10的机制以及它们之间的相互调节。结果表明：（1）STAT3在体内被伯氏疟原虫ANKA（PBA）感染激活，在体外被Heme感染激活。 (2)血红素通过STAT3途径上调HO-1和CXCL10的产生，并在体外转录水平上调节CXCL10。 (3)HO-1转录受CXCL10正向调控。 (4) HO-1 调节 STAT3 信号传导。我们的数据表明，Heme/HO-1、CXCL10/CXCR3和STAT3分子以及相关信号通路在重症疟疾的发病机制中发挥着非常重要的作用。我们的结论是，这些因素是相互调节的，并为开发潜在的新型治疗靶点提供了新的机会，这些靶点可用于补充传统的疟疾预防和治疗方法，改善临床结果，同时降低疟疾死亡率。我们的最终目标是开发针对与致命疟疾发展相关的血红素或 CXCL10 相关生物信号分子的新疗法。
The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated. We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line. The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling. Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.
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影响因子：
4.7
作者：
Belcher, John D.;Vineyard, Julie V.;Bruzzone, Carol M.;Chen, Chunsheng;Beckman, Joan D.;Nguyen, Julia;Steer, Clifford J.;Vercellotti, Gregory M.
通讯作者：
Vercellotti, Gregory M.
影响因子：
4.4
作者：
Hansen, Diana S.;Bernard, Nicholas J.;Schofield, Louis
通讯作者：
Schofield, Louis
影响因子：
6.6
作者：
Kotsch, Katja;Martins, Paulo N. A.;Volk, Hans-Dieter
通讯作者：
Volk, Hans-Dieter
影响因子：
15.9
作者：
Belcher, JD;Mahaseth, H;Vercellotti, GM
通讯作者：
Vercellotti, GM
影响因子：
12.4
作者：
Ke, Bibo;Shen, Xiu-Da;Kupiec-Weglinski, Jerzy W.
通讯作者：
Kupiec-Weglinski, Jerzy W.