Higashi H, Suzuki Y, Mukaida N, Takahashi N, Miyamoto D, Matsushima K
Department of Pharmacology, Cancer Research Institute, Kanazawa University, Japan.
Infect Immun. 1997 Apr;65(4):1223-7. doi: 10.1128/iai.65.4.1223-1227.1997.
Accumulating evidence indicates that tumor necrosis factor alpha (TNF-alpha) is a principal mediator of endotoxin shock. We previously reported that the action as well as the production of TNF requires the adhesion of leukocytes to the endothelium through integrin beta2 and intercellular adhesion molecule 1. In order to elucidate the roles of the initial interaction of the leukocytes with the endothelium through the selectins, we have examined the effects of a ligand for L- and P-selectins, sulfatide, on endotoxin shock in mice. Consistent with previous reports, a single injection of a high dose of endotoxin caused acute lethality, marked hypotension, leukopenia, and elevation in serum TNF-alpha levels. Pretreatment with sulfatide prevented acute lethality and hypotension, but not leukopenia, with a concomitant reduction in the increase in serum TNF-alpha levels. Moreover, pretreatment with sulfatide inhibited lipopolysaccharide (LPS)-induced TNF-alpha production by a human monocytic cell line, THP-1, in a dose-dependent manner. These results suggest either that selectin is critically involved in conferring the responsiveness of leukocytes to LPS or that sulfatide interferes with the intracellular signaling pathway which leads to TNF-alpha gene activation.
越来越多的证据表明，肿瘤坏死因子α（TNF-α）是内毒素休克的主要介质。我们之前报道过，TNF的作用及其产生需要白细胞通过整合素β2和细胞间黏附分子1黏附于内皮细胞。为了阐明白细胞通过选择素与内皮细胞的初始相互作用的作用，我们研究了L-选择素和P-选择素的配体硫苷脂对小鼠内毒素休克的影响。与之前的报道一致，单次注射高剂量内毒素会导致急性致死、明显的低血压、白细胞减少以及血清TNF-α水平升高。硫苷脂预处理可预防急性致死和低血压，但不能预防白细胞减少，同时可降低血清TNF-α水平的升高。此外，硫苷脂预处理以剂量依赖的方式抑制人单核细胞系THP-1中脂多糖（LPS）诱导的TNF-α产生。这些结果表明，要么选择素在赋予白细胞对LPS的反应性中起关键作用，要么硫苷脂干扰了导致TNF-α基因激活的细胞内信号通路。
