Curran Colleen S, Demick Karen P, Mansfield John M
Department of Bacteriology, 1925 Willow Drive, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cell Immunol. 2006 Jul;242(1):23-30. doi: 10.1016/j.cellimm.2006.08.006. Epub 2006 Oct 10.
Lactoferrin (LF) is a component of innate immunity and is known to interact with accessory molecules involved in the TLR4 pathway, including CD14 and LPS binding protein, suggesting that LF may activate components of the TLR4 pathway. In the present study, we have asked whether bovine LF (bLF)-induced macrophage activation is TLR4-dependent. Both bLF and LPS stimulated IL-6 production and CD40 expression in RAW 264.7 macrophages and in BALB/cJ peritoneal exudate macrophages. However, in macrophages from congenic TLR4(-/-) C.C3-Tlr4(lps-d) mice, CD40 was not expressed while IL-6 secretion was increased relative to wild-type cells. The signaling components NF-kappaB, p38, ERK and JNK were activated in RAW 264.7 cells and BALB/cJ macrophages after bLF or LPS stimulation, demonstrating that the TLR4-dependent bLF activation pathway utilizes signaling components common to LPS activation. In TLR4 deficient macrophages, bLF-induced activation of NF-kappaB, p38, ERK and JNK whereas LPS-induced cell signaling was absent. We conclude from these studies that bLF induces limited and defined macrophage activation and cell signaling events via TLR4-dependent and -independent mechanisms. bLF-induced CD40 expression was TLR4-dependent whereas bLF-induced IL-6 secretion was TLR4-independent, indicating potentially separate pathways for bLF mediated macrophage activation events in innate immunity.
乳铁蛋白（LF）是固有免疫的一个组成部分，已知其可与Toll样受体4（TLR4）信号通路中的辅助分子相互作用，包括CD14和脂多糖结合蛋白，这表明LF可能激活TLR4信号通路的组成部分。在本研究中，我们探讨了牛乳铁蛋白（bLF）诱导的巨噬细胞激活是否依赖于TLR4。bLF和脂多糖均刺激RAW 264.7巨噬细胞和BALB/cJ腹膜渗出巨噬细胞产生白细胞介素-6（IL-6）并表达CD40。然而，在同基因TLR4基因敲除的C.C3-Tlr4（lps-d）小鼠的巨噬细胞中，CD40未表达，而IL-6分泌相对于野生型细胞增加。bLF或脂多糖刺激后，RAW 264.7细胞和BALB/cJ巨噬细胞中的信号转导成分核因子κB（NF-κB）、p38、细胞外信号调节激酶（ERK）和c-Jun氨基末端激酶（JNK）被激活，表明依赖TLR4的bLF激活途径利用了脂多糖激活所共有的信号转导成分。在TLR缺4陷的巨噬细胞中，bLF可诱导NF-κB、p38、ERK和JNK激活，而脂多糖诱导的细胞信号传导缺失。我们从这些研究中得出结论，bLF通过依赖TLR4和不依赖TLR4的机制诱导有限且特定的巨噬细胞激活和细胞信号转导事件。bLF诱导的CD40表达依赖于TLR4，而bLF诱导的IL-6分泌不依赖于TLR4，这表明在固有免疫中bLF介导的巨噬细胞激活事件可能存在不同的途径。
