Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, Kopf M, Katada Y, Tanaka T, Suemura M, Kishimoto T
Department of Medicine III, Osaka University Medical School, Suita City, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8222-6. doi: 10.1073/pnas.95.14.8222.
To investigate the direct role of interleukin (IL) 6 in the development of rheumatoid arthritis, IL-6-deficient (IL-6 -/-) mice were backcrossed for eight generations into C57BL/6 mice, a strain of mice with a genetic background of susceptibility for antigen-induced arthritis (AIA). Both histological and immunological comparisons were made between IL-6-deficient (IL-6 -/-) mice and wild-type (IL-6 +/+) littermates after the induction of AIA. Although all IL-6 +/+ mice developed severe arthritis, only mild arthritis was observed in IL-6 -/- mice. Safranin O staining demonstrated that articular cartilage was well preserved in IL-6 -/- mice, whereas it was destroyed completely in IL-6 +/+ mice. In addition, comparable mRNA expression for both IL-1beta and tumor necrosis factor alpha, but not for IL-6, was detected in the inflamed joints of IL-6 -/- mice, suggesting that IL-6 may play a more crucial role in cartilage destruction than either IL-1beta or tumor necrosis factor alpha. In immunological comparisons, both antigen-specific in vitro proliferative response in lymph node cells and in vivo antibody production were elicited in IL-6 -/- mice, but they were reduced to less than half of that found in IL-6 +/+ mice. Lymph node cells of IL-6 -/- mice produced many more Th2 cytokines than did IL-6 +/+ mice with either antigen-specific or nonspecific stimulation in in vitro culture. Taken together, these results indicate that IL-6 may play a key role in the development of AIA at the inductive as well as the effector phase, and the blockade of IL-6 is possibly beneficial in the treatment of rheumatoid arthritis.
为研究白细胞介素（IL）-6在类风湿性关节炎发病中的直接作用，将IL-6基因缺陷（IL-6 -/-）小鼠与C57BL/6小鼠回交八代，C57BL/6小鼠是一种对抗原诱导性关节炎（AIA）具有遗传易感性背景的小鼠品系。在诱导AIA后，对IL-6基因缺陷（IL-6 -/-）小鼠和野生型（IL-6 +/+）同窝小鼠进行了组织学和免疫学比较。尽管所有IL-6 +/+小鼠均发生了严重关节炎，但在IL-6 -/-小鼠中仅观察到轻度关节炎。番红O染色显示，IL-6 -/-小鼠的关节软骨保存良好，而在IL-6 +/+小鼠中则完全被破坏。此外，在IL-6 -/-小鼠的炎症关节中检测到IL-1β和肿瘤坏死因子α的mRNA表达相当，但未检测到IL-6的表达，这表明IL-6在软骨破坏中可能比IL-1β或肿瘤坏死因子α发挥更关键的作用。在免疫学比较中，IL-6 -/-小鼠的淋巴结细胞中诱导了抗原特异性体外增殖反应和体内抗体产生，但它们降至IL-6 +/+小鼠中的不到一半。在体外培养中，无论是抗原特异性还是非特异性刺激，IL-6 -/-小鼠的淋巴结细胞产生的Th2细胞因子都比IL-6 +/+小鼠多得多。综上所述，这些结果表明IL-6可能在AIA的诱导期和效应期发病中起关键作用，阻断IL-6可能对类风湿性关节炎的治疗有益。
