Bemelmans M H, Gouma D J, Buurman W A
Department of Surgery, Faculty II, University of Limburg, Maastricht, The Netherlands.
J Immunol. 1993 Mar 1;150(5):2007-17.
TNF, a cytokine with multiple properties, is known to be rapidly inactivated in vivo. In patients with septic shock and kidney malfunction, conflicting data have been reported regarding the presence of TNF in the circulation. Recently, we have shown that these differences can be the result of the detection of free TNF vs TNF complexed with soluble TNF-R. Enhanced levels of soluble TNF-R have been reported in patients with kidney malfunction. Because the kidney is thought to play an important role in TNF and TNF-R metabolism, we investigated the influence of bilateral nephrectomy on TNF clearance and TNF-R regulation in a murine model. The data obtained show that bilateral nephrectomy results in circulating levels of immunologically detectable (ELISA), but not biologically active (bioassay), TNF. Injection of endotoxin results in significantly higher levels of immunologically detectable TNF in bilaterally nephrectomized mice, compared with sham-operated mice, whereas biologically active levels were similar. To investigate the roles of TNF-R1 (P55) and TNF-R2 (P75) in this process, clearance of TNF was studied by injection of murine and human TNF. Murine TNF injection leads to comparable clearance of bioactive TNF in nephrectomized and sham-operated mice (t1/2 = approximately 12 min). However, clearance of immunologically detectable murine TNF is significantly slower in nephrectomized mice, compared with sham-operated mice (t1/2 = 96 min vs 26 min, respectively; p < 0.05). Administration of human TNF results in a significantly lower clearance in nephrectomized mice, compared with sham-operated mice (t1/2 = 108 min vs 25 min, respectively; p < 0.05). This is observed for both bioactive human TNF and immunologically detectable human TNF. Based on the fact that murine TNF-R1 (55 kDa) has a similar affinity for murine and human TNF, whereas murine TNF-R2 (75 kDa) shows affinity only for murine TNF, the data obtained suggest an important role for TNF-R2 in inactivation and clearance of TNF by the kidney. Moreover, the data suggest that kidney malfunction affects TNF clearance, leading to increased amounts of circulating TNF-TNF-R complexes, which could function as a slow release reservoir for TNF.
肿瘤坏死因子（TNF）是一种具有多种特性的细胞因子，已知其在体内会迅速失活。在感染性休克和肾功能不全的患者中，关于循环中TNF的存在情况，已有相互矛盾的数据报道。最近，我们发现这些差异可能是由于检测游离TNF与与可溶性TNF受体结合的TNF复合物所致。据报道，肾功能不全患者的可溶性TNF受体水平升高。由于肾脏被认为在TNF和TNF受体代谢中起重要作用，我们在小鼠模型中研究了双侧肾切除对TNF清除和TNF受体调节的影响。获得的数据表明，双侧肾切除导致循环中可通过免疫检测（ELISA）到的TNF水平升高，但生物活性（生物测定）的TNF水平未升高。与假手术小鼠相比，注射内毒素后双侧肾切除小鼠中免疫检测到的TNF水平明显更高，而生物活性水平相似。为了研究TNF受体1（P55）和TNF受体2（P75）在此过程中的作用，通过注射小鼠和人TNF来研究TNF的清除情况。注射小鼠TNF后，肾切除小鼠和假手术小鼠中生物活性TNF的清除情况相当（半衰期约为12分钟）。然而，与假手术小鼠相比，肾切除小鼠中免疫检测到的小鼠TNF的清除明显较慢（半衰期分别为96分钟和26分钟；p<0.05）。与人TNF相比，肾切除小鼠中其清除率明显低于假手术小鼠（半衰期分别为108分钟和25分钟；p<0.05）。生物活性人TNF和免疫检测到的人TNF均观察到这种情况。基于小鼠TNF受体1（55 kDa）对小鼠和人TNF具有相似亲和力，而小鼠TNF受体2（75 kDa）仅对小鼠TNF具有亲和力这一事实，获得的数据表明TNF受体2在肾脏对TNF的失活和清除中起重要作用。此外，数据表明肾功能不全会影响TNF的清除，导致循环中TNF-TNF受体复合物的量增加，这可能作为TNF的缓释储存库。
