Acton R D, Dahlberg P S, Uknis M E, Klaerner H G, Fink G S, Norman J G, Dunn D L
Department of Surgery, University of Minnesota, Minneapolis, USA.
Arch Surg. 1996 Nov;131(11):1216-21. doi: 10.1001/archsurg.1996.01430230098017.
To determine the effect of targeted disruption of the cellular receptors of either tumor necrosis factor alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta) during experimental gram-negative bacterial infection and endotoxemia.
Transgenic (knockout [KO]) mice deficient in either the p55 TNF receptor (TNF RI) or the p80 IL-1 receptor (IL-1 RI) were challenged with intravenous lipopolysaccharide (endotoxin) or intraperitoneal live Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Serum endotoxin levels and quantitative blood cultures were monitored at multiple times during infection.
Surgical infectious disease research laboratory.
Mortality, results of quantitative blood cultures, and serum endotoxin levels.
Both TNF and IL-1 RI KO mice were resistant to endotoxin challenge (0% mortality for both groups) compared with control mice (100% mortality [P < .01]). In contrast, only the IL-1 RI KO mice were resistant to infection caused by viable gram-negative bacteria (43% mortality) compared with control mice (100% mortality [P < .01]). Infection led to 100% mortality in TNF RI KO mice. The IL-1 RI KO mice exhibited less bacteremia and diminished endotoxemia compared with control and TNF RI KO mice 18 and 24 hours after infection.
The absence of either the TNF or the IL-1 RI receptor prevents cellular activation by each respective cytokine. Absence confers protection against intravenous endotoxin, which stimulates massive rapid release of cytokines into the systemic circulation. However, bacterial infection within the peritoneal cavity is known to cause more delayed cytokine release, and cytokines may act at the site of infection to enhance host defenses. We believe that IL-1 signaling may be more critical in provoking lethal systemic toxic effects than TNF signaling. However, TNF signaling may be an important component of host defense enhancement at the local site of infection.
确定在实验性革兰氏阴性菌感染和内毒素血症期间，肿瘤坏死因子α（TNF-α）或白细胞介素-1β（IL-1β）细胞受体的靶向破坏作用。
用静脉注射脂多糖（内毒素）或腹腔注射活的大肠杆菌0111:B4对缺乏p55 TNF受体（TNF RI）或p80 IL-1受体（IL-1 RI）的转基因（基因敲除[KO]）小鼠进行攻击。连续7天每日评估死亡率。在感染期间多次监测血清内毒素水平和定量血培养结果。
外科传染病研究实验室。
死亡率、定量血培养结果和血清内毒素水平。
与对照小鼠（100%死亡率[P <.01]）相比，TNF和IL-1 RI基因敲除小鼠对内毒素攻击均有抗性（两组死亡率均为0%）。相比之下，与对照小鼠（100%死亡率[P <.01]）相比，只有IL-1 RI基因敲除小鼠对活的革兰氏阴性菌引起的感染有抗性（死亡率43%）。感染导致TNF RI基因敲除小鼠100%死亡。与对照小鼠和TNF RI基因敲除小鼠相比，感染后18和24小时，IL-1 RI基因敲除小鼠的菌血症较少，内毒素血症减轻。
TNF或IL-1 RI受体的缺失可防止相应细胞因子激活细胞。这种缺失可提供针对静脉内毒素的保护，内毒素会刺激细胞因子大量快速释放到体循环中。然而，已知腹腔内的细菌感染会导致细胞因子释放更延迟，并且细胞因子可能在感染部位起作用以增强宿主防御。我们认为，IL-1信号传导在引发致命的全身毒性作用方面可能比TNF信号传导更关键。然而，TNF信号传导可能是感染局部部位宿主防御增强的重要组成部分。
