Papasian Christopher J, Silverstein Richard, Gao Jian Jun, Bamberger David M, Morrison David C
Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 64108, USA.
Infect Immun. 2002 Dec;70(12):6628-37. doi: 10.1128/IAI.70.12.6628-6637.2002.
The murine D-galactosamine (D-gal) model of tumor necrosis factor alpha (TNF-alpha) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-alpha to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. D-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-alpha antibody protected D-gal-treated, E. faecalis-infected mice, implicating TNF-alpha in the lethal response to E. faecalis infection in D-gal-treated mice. Circulating TNF-alpha was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-alpha were detected within 3 h, suggesting that localized TNF-alpha production contributed to the lethal response to E. faecalis infection in D-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-alpha response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-alpha. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-alpha response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-alpha production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-alpha production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.
小鼠肿瘤坏死因子α（TNF-α）超敏化的D-半乳糖胺（D-gal）模型被用作初始工具，以研究TNF-α对粪肠球菌致死性腹腔内（i.p.）感染的潜在作用。D-gal使小鼠对致死性粪肠球菌感染敏感，而地塞米松和中和抗TNF-α抗体可保护经D-gal处理、感染粪肠球菌的小鼠，这表明TNF-α参与了D-gal处理小鼠对粪肠球菌感染的致死反应。腹腔内感染粪肠球菌后至少8小时检测不到循环TNF-α，尽管在3小时内检测到低水平的腹腔TNF-α，这表明局部TNF-α产生促成了D-gal处理小鼠对粪肠球菌感染的致死反应。尽管腹腔内感染粪肠球菌未能诱导可检测到的全身性TNF-α反应，但在感染后3小时内检测到循环白细胞介素-6（IL-6）。在感染后一小时内，在腹腔内也检测到了IL-6，早于腹腔TNF-α的出现。与体内结果形成鲜明对比的是，粪肠球菌在体外可诱导小鼠腹腔巨噬细胞和RAW 264.7细胞系产生强烈而快速的TNF-α反应。这使我们推测，在体内，IL-6抑制了对粪肠球菌感染的TNF-α产生。体外实验表明，IL-6对经粪肠球菌刺激的RAW细胞产生TNF-α具有统计学上显著但适度的抑制作用。总体而言，这些数据表明，急性致死性粪肠球菌感染似乎诱导了一种不寻常的细胞因子反应，其特征与先前描述的大多数其他革兰氏阳性和革兰氏阴性细菌不同。
