Department of Environmental Medicine, Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):591-8. doi: 10.1161/ATVBAHA.109.197343. Epub 2009 Dec 30.
To investigate the presence and role of NF-kappaB proteins in megakaryocytes and platelets. The nuclear factor-kappaB (NF-kappaB) transcription factor family is well known for its role in eliciting inflammation and promoting cell survival. We discovered that human megakaryocytes and platelets express the majority of NF-kappaB family members, including the regulatory inhibitor-kappaB (I-kappaB) and I-kappa kinase (IKK) molecules.
Anucleate platelets exposed to NF-kappaB inhibitors demonstrated impaired fundamental functions involved in repairing vascular injury and thrombus formation. Specifically, NF-kappaB inhibition diminished lamellapodia formation, decreased clot retraction times, and reduced thrombus stability. Moreover, inhibition of I-kappaB-alpha phosphorylation (BAY-11-7082) reverted fully spread platelets back to a spheroid morphology. Addition of recombinant IKK-beta or I-kappaB-alpha protein to BAY inhibitor-treated platelets partially restored platelet spreading in I-kappaB-alpha inhibited platelets, and addition of active IKK-beta increased endogenous I-kappaB-alpha phosphorylation levels.
These novel findings support a crucial and nonclassical role for the NF-kappaB family in modulating platelet function and reveal that platelets are sensitive to NF-kappaB inhibitors. As NF-kappaB inhibitors are being developed as antiinflammatory and anticancer agents, they may have unintended effects on platelets. On the basis of these data, NF-kappaB is also identified as a new target to dampen unwanted platelet activation.
研究 NF-κB 蛋白在巨核细胞和血小板中的存在和作用。核因子-κB（NF-κB）转录因子家族因其在引发炎症和促进细胞存活方面的作用而广为人知。我们发现，人类巨核细胞和血小板表达大多数 NF-κB 家族成员，包括调节抑制剂-κB（I-κB）和 I-κB 激酶（IKK）分子。
无核血小板暴露于 NF-κB 抑制剂后，其参与修复血管损伤和血栓形成的基本功能受损。具体而言，NF-κB 抑制减少了伪足形成，缩短了血栓回缩时间，并降低了血栓稳定性。此外，抑制 I-κB-α磷酸化（BAY-11-7082）可使完全展开的血小板完全恢复为球形形态。将重组 IKK-β或 I-κB-α蛋白添加到 BAY 抑制剂处理的血小板中，可部分恢复 I-κB-α抑制的血小板中的血小板扩展，并且添加活性 IKK-β可增加内源性 I-κB-α磷酸化水平。
这些新发现支持 NF-κB 家族在调节血小板功能中的关键和非经典作用，并表明血小板对 NF-κB 抑制剂敏感。由于 NF-κB 抑制剂正在被开发为抗炎和抗癌药物，它们可能对血小板产生意想不到的影响。基于这些数据，NF-κB 也被确定为抑制不必要的血小板激活的新靶标。
