Bemelmans M H, Gouma D J, Buurman W A
Department of Surgery, Faculty II, University of Limburg, Maastricht, The Netherlands.
J Immunol. 1993 Nov 15;151(10):5554-62.
TNF, a primary mediator of the response to infection, can be injurious to the organism when present in excessive quantities. Circulating soluble TNF receptors (sTNFR) appear to represent a natural mechanism that protects against circulating TNF. Two soluble TNF receptors (sTNFR-P55 and sTNFR-P75) circulate in vivo and are up-regulated in response to endotoxin. In this study, we investigated the kinetics of LPS-induced sTNFR release and the role of the cytokines TNF, leukemia inhibiting factor, IFN-gamma, and IL-1 in this process. The results show that LPS injection results in a rapid increase in levels of both sTNFR. Although sTNFR-P55 decreases after a peak at 30 min, sTNFR-P75 levels show a peak after 4 to 8 h, after which they slowly diminish. Both human TNF and murine TNF are capable of increasing levels of both sTNFR. Blocking circulating TNF by administration of 3 different anti-TNF agents before LPS injection (mAb to murine TNF, sTNFR55-Fc or sTNFR75-Fc) results in a significant increase of sTNFR-P55 levels, whereas only both sTNFR-Fc constructs also significantly increase sTNFR-P75 levels. Although IL-1 receptor antagonist pretreatment before LPS has no effect on TNF or sTNFR levels, leukemia inhibiting factor pretreatment significantly increases sTNFR-P55 levels. Pretreatment with anti IFN-gamma mAb before LPS results in a significant reduction in TNF and sTNFR-P55 levels, but sTNFR-P75 levels are significantly increased. Our data show that both sTNFR can be up-regulated by LPS and TNF. The influence of TNF, leukemia inhibiting factor, IL-1, and IFN-gamma on the kinetics of LPS-induced circulating sTNFR is discussed in the context of the pathophysiology of LPS-induced disease.
肿瘤坏死因子（TNF）是感染反应的主要介质，当体内含量过高时，会对机体造成损害。循环中的可溶性TNF受体（sTNFR）似乎是一种抵御循环中TNF的天然机制。两种可溶性TNF受体（sTNFR-P55和sTNFR-P75）在体内循环，并在内毒素刺激下上调。在本研究中，我们调查了脂多糖（LPS）诱导的sTNFR释放动力学，以及细胞因子TNF、白血病抑制因子、干扰素-γ（IFN-γ）和白细胞介素-1（IL-1）在此过程中的作用。结果显示，注射LPS会导致两种sTNFR水平迅速升高。尽管sTNFR-P55在30分钟达到峰值后下降，但sTNFR-P75水平在4至8小时后达到峰值，之后缓慢下降。人TNF和鼠TNF均能增加两种sTNFR的水平。在注射LPS前给予3种不同的抗TNF药物（抗鼠TNF单克隆抗体、sTNFR55-Fc或sTNFR75-Fc）阻断循环中的TNF，会导致sTNFR-P55水平显著升高，而只有两种sTNFR-Fc构建体也能显著提高sTNFR-P75水平。尽管在LPS注射前用IL-1受体拮抗剂预处理对TNF或sTNFR水平无影响，但白血病抑制因子预处理能显著提高sTNFR-P55水平。在LPS注射前用抗IFN-γ单克隆抗体预处理会导致TNF和sTNFR-P55水平显著降低，但sTNFR-P75水平显著升高。我们的数据表明，两种sTNFR均可被LPS和TNF上调。在LPS诱导疾病的病理生理学背景下，讨论了TNF、白血病抑制因子、IL-1和IFN-γ对LPS诱导的循环sTNFR动力学的影响。
