He Rong L, Zhou Jian, Hanson Crystal Z, Chen Jia, Cheng Ni, Ye Richard D
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Blood. 2009 Jan 8;113(2):429-37. doi: 10.1182/blood-2008-03-139923. Epub 2008 Oct 24.
The acute-phase protein serum amyloid A (SAA) is commonly considered a marker for inflammatory diseases; however, its precise role in inflammation and infection, which often result in neutrophilia, remains ambiguous. In this study, we demonstrate that SAA is a potent endogenous stimulator of granulocyte colony-stimulated factor (G-CSF), a principal cytokine-regulating granulocytosis. This effect of SAA is dependent on Toll-like receptor 2 (TLR2). Our data demonstrate that, in mouse macrophages, both G-CSF mRNA and protein were significantly increased after SAA stimulation. The induction of G-CSF was blocked by an anti-TLR2 antibody and markedly decreased in the TLR2-deficient macrophages. SAA stimulation results in the activation of nuclear factor-kappaB and binding activity to the CK-1 element of the G-CSF promoter region. In vitro reconstitution experiments also support that TLR2 mediates SAA-induced G-CSF expression. In addition, SAA-induced secretion of G-CSF was sensitive to heat and proteinase K treatment, yet insensitive to polymyxin B treatment, indicating that the induction is a direct effect of SAA. Finally, our in vivo studies confirmed that SAA treatment results in a significant increase in plasma G-CSF and neutrophilia, whereas these responses are ablated in G-CSF- or TLR2-deficient mice.
急性期蛋白血清淀粉样蛋白A（SAA）通常被认为是炎症性疾病的标志物；然而，其在炎症和感染（常导致中性粒细胞增多）中的精确作用仍不明确。在本研究中，我们证明SAA是粒细胞集落刺激因子（G-CSF，一种调节粒细胞增多的主要细胞因子）的强效内源性刺激物。SAA的这种作用依赖于Toll样受体2（TLR2）。我们的数据表明，在小鼠巨噬细胞中，SAA刺激后G-CSF的mRNA和蛋白均显著增加。G-CSF的诱导被抗TLR2抗体阻断，并且在TLR2缺陷型巨噬细胞中显著降低。SAA刺激导致核因子-κB激活以及与G-CSF启动子区域的CK-1元件的结合活性。体外重组实验也支持TLR2介导SAA诱导的G-CSF表达。此外，SAA诱导的G-CSF分泌对热和蛋白酶K处理敏感，但对多粘菌素B处理不敏感，表明这种诱导是SAA的直接作用。最后，我们的体内研究证实，SAA处理导致血浆G-CSF显著增加和中性粒细胞增多，而在G-CSF或TLR2缺陷型小鼠中这些反应消失。
