Sunil Vasanthi R, Patel Kinal J, Nilsen-Hamilton Marit, Heck Diane E, Laskin Jeffrey D, Laskin Debra L
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
Exp Mol Pathol. 2007 Oct;83(2):177-87. doi: 10.1016/j.yexmp.2007.03.004. Epub 2007 Mar 30.
Acute endotoxemia is associated with production of acute phase proteins which regulate inflammatory responses to tissue injury. Consistent with DNA microarray experiments, we found that acute endotoxemia, induced by administration of lipopolysaccharide (LPS) to mice (1 mg/kg) or rats (5 mg/kg), resulted in increased expression of the hepatic acute phase protein, lipocalin 24p3, which was evident within 4 h and persisted for 24-48 h. Increases in 24p3 expression were also observed in the lung after LPS administration, as well as in isolated liver and lung macrophages, and Type II alveolar epithelial cells. The actions of LPS are dependent, in part, on Toll-like receptor (TLR) proteins. Macrophages from C3H/HeJ mice, which possess a nonfunctional TLR-4, expressed low levels of 24p3 mRNA when compared to cells from control C3H/OuJ mice. Whereas LPS administration increased 24p3 expression in lung and liver macrophages from control C3H/OuJ mice, minimal effects were observed in TLR-4 mutant mice demonstrating that TLR-4 is important in regulating 24p3 expression during acute endotoxemia. Promoters for genes encoding lipocalin proteins including 24p3 contain consensus sequences for transcription factors including NF-kappaB, and C/EBP. Acute endotoxemia resulted in NF-kappaB nuclear binding activity in both alveolar macrophages and Type II cells. In contrast, C/EBP activation was evident only in Type II cells, suggesting differential effects of LPS on these cell types. These data suggest that the acute phase response to acute endotoxemia involves induction of 24p3 in both the lung and liver. This protein may be important in restoring tissue homeostasis following LPS-induced injury.
急性内毒素血症与急性期蛋白的产生相关，急性期蛋白可调节对组织损伤的炎症反应。与DNA微阵列实验结果一致，我们发现，给小鼠（1mg/kg）或大鼠（5mg/kg）注射脂多糖（LPS）诱导急性内毒素血症后，肝脏急性期蛋白lipocalin 24p3的表达增加，4小时内即可明显观察到，且持续24 - 48小时。LPS给药后，在肺组织、分离的肝巨噬细胞和肺巨噬细胞以及II型肺泡上皮细胞中也观察到24p3表达增加。LPS的作用部分依赖于Toll样受体（TLR）蛋白。与对照C3H/OuJ小鼠的细胞相比，C3H/HeJ小鼠（其TLR - 4无功能）的巨噬细胞表达的24p3 mRNA水平较低。虽然LPS给药可增加对照C3H/OuJ小鼠肺和肝巨噬细胞中24p3的表达，但在TLR - 4突变小鼠中观察到的影响极小，这表明TLR - 4在急性内毒素血症期间调节24p3表达中起重要作用。包括24p3在内的lipocalin蛋白编码基因的启动子含有转录因子NF - κB和C/EBP的共有序列。急性内毒素血症导致肺泡巨噬细胞和II型细胞中NF - κB核结合活性增加。相反，C/EBP激活仅在II型细胞中明显，表明LPS对这些细胞类型有不同的影响。这些数据表明，对急性内毒素血症的急性期反应涉及肺和肝中24p3的诱导。这种蛋白可能在LPS诱导的损伤后恢复组织稳态中起重要作用。
