Cleaved fibrinogen products bind TLR4:LY96

Fibrinogen, in addition to its role in coagulation, is also an acute phase protein of inflammation which can induce a cytokine production acting as an endogenous ligand for toll-like receptor 4 (TLR4) expressed on cells including macrophages and airway epithelial cells (Millien VO et al., 2013; Kuhns DB et al., 2007; Smiley ST et al., 2001). In human macrophages fibrinogen stimulated interleukin IL6 expression and extracellular signal-related kinase (ERK) phosphorylation ((Hodgkinson CP et al., 2008). In human embryonic kidney 293 (HEK293)-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk1 and AP1 (Hodgkinson CP et al., 2008). Moreover, proteinases, such as thrombin, can cleave fibrinogen. In mice, exposure to endogenous or exogenous proteinases lead to hyperactivation of an antifungal pathway and lead to allergic airway inflammation through activation of TLR4-dependent signaling pathway by fibrinogen cleaved products (Millien VO et al., 2013)

纤维蛋白原，除其在凝血过程中的作用外，亦为炎症的急性期蛋白，能够诱导细胞因子产生，充当表达于包括巨噬细胞和气道上皮细胞在内的细胞上的Toll样受体4（TLR4）的内源性配体（Millien VO 等人，2013；Kuhns DB 等人，2007；Smiley ST 等人，2001）。在人类巨噬细胞中，纤维蛋白原刺激白细胞介素IL6的表达和细胞外信号调节激酶（ERK）的磷酸化（Hodgkinson CP 等人，2008）。在表达TLR4的人类胚胎肾细胞系293（HEK293）-CD14-MD2细胞中，纤维蛋白原诱导了ERK1、p38alpha和JNK的显著磷酸化，并激活了转录因子NFkappaB、Elk1和AP1（Hodgkinson CP 等人，2008）。此外，蛋白酶，如凝血酶，能够裂解纤维蛋白原。在老鼠中，暴露于内源性或外源性蛋白酶会导致抗真菌途径的过度激活，并通过纤维蛋白原裂解产物激活TLR4依赖性信号通路，进而引发过敏性气道炎症（Millien VO 等人，2013）。