Tsujimoto Hironori, Ono Satoshi, Majima Takashi, Kawarabayashi Nobuaki, Takayama Eiji, Kinoshita Manabu, Seki Shuhji, Hiraide Hoshio, Moldawer Lyle L, Mochizuki Hidetaka
Department of Surgery I, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan.
Shock. 2005 Jan;23(1):39-44. doi: 10.1097/01.shk.0000145936.31967.d7.
Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). TLR-4 expression on monocytes/macrophages was examined in patients with sepsis and in murine peritonitis and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before their exposure to LPS resulted in a significant dose-dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil-derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.
高度活化的中性粒细胞通过释放中性粒细胞弹性蛋白酶（NE）在介导脓毒症器官损伤中起关键作用。Toll样受体（TLR）在宿主抵御入侵微生物的防御中起重要作用，其信号通路对促炎反应的激活至关重要。然而，脓毒症期间TLR表达与宿主防御机制之间的关系尚未完全阐明。在本文中，我们研究了人类脓毒症和小鼠腹膜炎（CLP）中趋化因子（MIP-2）、TLR-4和NE表达之间的关系。检测了脓毒症患者和小鼠腹膜炎中单核细胞/巨噬细胞上的TLR-4表达，两者均显著增加。与假手术小鼠相比，腹膜炎小鼠支气管肺泡细胞和肝单核细胞中LPS诱导的MIP-2产生也显著增加。巨噬细胞系RAW 264.7细胞在暴露于LPS之前用NE抑制剂预处理导致MIP-2产生显著的剂量依赖性降低，这与用TLR-4抗体预处理后的情况相当。此外，NE和LPS均上调人外周血单核细胞上的TLR-4表达。因此，脓毒症中趋化因子诱导的中性粒细胞募集可能导致趋化因子产生进一步增加和TLR-4表达增加。中性粒细胞衍生的NE可能与单核细胞/巨噬细胞TLR-4表达增加有关，从而作为不同细胞群体间炎症反应的正反馈回路。
