Amura C R, Kamei T, Ito N, Soares M J, Morrison D C
Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.
J Immunol. 1998 Sep 1;161(5):2552-60.
LPS binding to its receptor(s) on macrophages induces the synthesis of inflammatory mediators involved in septic shock. While the signaling mechanism(s) remains to be fully defined, the human LPS-binding protein (LBP) is known to regulate responses to LPS by facilitating its binding to CD14 on human monocytes. The structurally related bactericidal permeability increasing protein (BPI) differs from LBP by inhibiting LPS-induced human monocyte activation. We have demonstrated that, unlike the human monocyte response to LPS, both LBP and BPI inhibited LPS-stimulated TNF-alpha production in mouse peritoneal macrophages. In contrast, LPS-dependent nitric oxide release was not affected by LBP. LPS induces the phosphorylation of a number of proteins in a dose and time-dependent manner, however, the pattern of LPS-induced phosphorylation was not reduced by either LBP or BPI under conditions that result in selective TNF-alpha inhibition. Further, activation of the transcription factor NF-kappaB in response to LPS was also not modified by either LBP or BPI. Finally, no differences were detected in TNF-alpha or inducible nitric oxide synthase mRNA accumulations induced by LPS in the presence or absence of either protein, whereas a slight decreased mRNA stability was observed in the group with LPS treatment. These results would suggest that many of the early signaling events contribute to LPS-induced macrophage signaling at a point preceding the divergence of pathways that differentially regulate TNF-alpha and NO production.
脂多糖（LPS）与巨噬细胞上的受体结合会诱导参与脓毒性休克的炎症介质的合成。虽然信号传导机制仍有待完全明确，但已知人脂多糖结合蛋白（LBP）通过促进LPS与人单核细胞上的CD14结合来调节对LPS的反应。结构相关的杀菌通透性增加蛋白（BPI）与LBP不同，它能抑制LPS诱导的人单核细胞活化。我们已经证明，与人类单核细胞对LPS的反应不同，LBP和BPI都能抑制LPS刺激的小鼠腹腔巨噬细胞中肿瘤坏死因子-α（TNF-α）的产生。相比之下，LPS依赖性一氧化氮释放不受LBP影响。LPS以剂量和时间依赖性方式诱导多种蛋白质磷酸化，然而，在导致选择性TNF-α抑制的条件下，LBP或BPI均未降低LPS诱导的磷酸化模式。此外，LBP或BPI也未改变LPS诱导的转录因子核因子-κB（NF-κB）的活化。最后，在有或没有这两种蛋白质的情况下，LPS诱导的TNF-α或诱导型一氧化氮合酶mRNA积累均未检测到差异，而在LPS处理组中观察到mRNA稳定性略有下降。这些结果表明，许多早期信号事件在差异调节TNF-α和一氧化氮（NO）产生的信号通路分歧之前的某个点上对LPS诱导的巨噬细胞信号传导起作用。
