Regulatory effects of TLR2 on megakaryocytic cell function
Regulatory effects of TLR2 on megakaryocytic cell function
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DOI：
10.1182/blood-2010-09-304949
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发表时间：
2011-06-02
期刊：
影响因子：
20.3
通讯作者：
Freedman, Jane E.
中科院分区：
文献类型：
--
作者：
Beaulieu, Lea M.;Lin, Elaine;Freedman, Jane E.
TLR2是一种功能性炎症相关受体，表达于巨核细胞和血小板上，可导致感染和免疫介导的血小板活化；然而，该受体在巨核细胞中的作用尚不清楚。利用MEG-01细胞和小鼠巨核细胞，我们发现TLR2的特异性配体Pam3CSK4激活了已知的TLRs下游通路--NF-kappa B、ERK-MAPK和PI3K/Akt通路。此外，与巨核细胞成熟相关的转录因子，GATA-1，NF-E2，以及哺乳动物雷帕霉素靶标(MTOR)，都在Pam3CSK4的存在下增加。Pam3CSK4对巨核细胞成熟的影响通过TLR2依赖的刺激增加DNA含量和与细胞外基质蛋白的黏附来证实。此外，刺激TLR2还导致活性氧(ROS)生成增加。巨核细胞经TLR2刺激后，通过NF-kappa B、PI3K/Akt和ERK-MAPK途径上调了GP1b、CD41、MCP-1、COX2、NF-kappa B1和TLR2的基因表达和蛋白水平。用Pam3CSK4治疗野生型小鼠后，血小板水平恢复到正常水平，巨核细胞成熟度增加，这在TLR2(-/-)小鼠中没有发生。因此，炎症通过TLR2促进巨核细胞成熟，调节巨核细胞表型，参与炎症与止血的相互关系。(血。2011；117(22)：5963-5974)
TLR2, a functional, inflammatory-related receptor, is known to be expressed on megakaryocytes and platelets and to lead to infection and immune-mediated activation of platelets; however, the role of this receptor in megakaryocytes is not understood. Using Meg-01 cells and mouse megakaryocytes, we found that NF kappa B, ERK-MAPK, and PI3K/Akt pathways, known downstream pathways of TLRs, are activated by Pam3CSK4, a TLR2-specific ligand. In addition, transcription factors associated with megakaryocyte maturation, GATA-1, NF-E2, and mammalian target of rapamycin (mTOR), are all increased in the presence of Pam3CSK4. The effect of Pam3CSK4 on megakaryocyte maturation was verified by the increase in DNA content and adhesion to extracellular matrix proteins by TLR2-dependent stimulation. In addition, TLR2 stimulation resulted in an increase in reactive oxygen species (ROS) production. Gene expression and protein levels of GP1b, CD41, MCP-1, COX2, NF kappa B1, and TLR2 were up-regulated in megakaryocytes after TLR2 stimulation through NF kappa B, PI3K/Akt, and ERK-MAPK pathways. Treatment of wild-type mice with Pam3CSK4 resulted in a return to normal platelet levels and an increase in megakaryocyte maturation, which did not occur in the TLR2(-/-) mice. Therefore, inflammation, through TLR2, can increase maturation and modulate the phenotype of megakaryocytes, contributing to the interrelationship between inflammation and hemostasis. (Blood. 2011; 117(22): 5963-5974)