Koch A E, Kunkel S L, Harlow L A, Mazarakis D D, Haines G K, Burdick M D, Pope R M, Walz A, Strieter R M
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
J Clin Invest. 1994 Sep;94(3):1012-8. doi: 10.1172/JCI117414.
We and others have shown that cells obtained from inflamed joints of rheumatoid arthritis (RA) patients produce interleukin-8, a potent chemotactic cytokine for neutrophils (PMNs). However, IL-8 accounted for only 40% of the chemotactic activity for PMNs found in these synovial fluids. Currently, we have examined the production of the novel PMN chemotactic cytokine, epithelial neutrophil activating peptide-78 (ENA-78), using peripheral blood, synovial fluid, and synovial tissue from 70 arthritic patients. RA ENA-78 levels were greater in RA synovial fluid (239 +/- 63 ng/ml) compared with synovial fluid from other forms of arthritis (130 +/- 118 ng/ml) or osteoarthritis (2.6 +/- 1.8 ng/ml) (P < 0.05). RA peripheral blood ENA-78 levels (70 +/- 26 ng/ml) were greater than normal peripheral blood levels (0.12 +/- 0.04 ng/ml) (P < 0.05). Anti-ENA-78 antibodies neutralized 42 +/- 9% (mean +/- SE) of the chemotactic activity for PMNs found in RA synovial fluids. Isolated RA synovial tissue fibroblasts in vitro constitutively produced significant levels of ENA-78, and this production was further augmented when stimulated with tumor necrosis factor-alpha (TNF-alpha). In addition RA and osteoarthritis synovial tissue fibroblasts as well as RA synovial tissue macrophages were found to constitutively produce ENA-78. RA synovial fluid mononuclear cells spontaneously produced ENA-78, which was augmented in the presence of lipopolysaccharide. Immunohistochemical localization of ENA-78 from the synovial tissue of patients with arthritis or normal subjects showed that the predominant cellular source of this chemokine was synovial lining cells, followed by macrophages, endothelial cells, and fibroblasts. Synovial tissue macrophages and fibroblasts were more ENA-78 immunopositive in RA than in normal synovial tissue (P < 0.05). These results, which are the first demonstration of ENA-78 in a human disease state, suggest that ENA-78 may play an important role in the recruitment of PMNs in the milieu of the inflamed joint of RA patients.
我们和其他人已经表明，从类风湿性关节炎（RA）患者发炎关节中获得的细胞会产生白细胞介素-8，这是一种对中性粒细胞（PMN）具有强大趋化作用的细胞因子。然而，IL-8仅占这些滑液中PMN趋化活性的40%。目前，我们使用70例关节炎患者的外周血、滑液和滑膜组织，检测了新型PMN趋化细胞因子上皮中性粒细胞激活肽-78（ENA-78）的产生情况。与其他形式关节炎的滑液（130±118 ng/ml）或骨关节炎的滑液（2.6±1.8 ng/ml）相比，RA滑液中的ENA-78水平更高（239±63 ng/ml）（P<0.05）。RA外周血ENA-78水平（70±26 ng/ml）高于正常外周血水平（0.12±0.04 ng/ml）（P<0.05）。抗ENA-78抗体中和了RA滑液中PMN趋化活性的42±9%（平均值±标准误）。体外分离的RA滑膜组织成纤维细胞持续产生显著水平的ENA-78，当用肿瘤坏死因子-α（TNF-α）刺激时，这种产生会进一步增加。此外，发现RA和骨关节炎滑膜组织成纤维细胞以及RA滑膜组织巨噬细胞持续产生ENA-78。RA滑液单核细胞自发产生ENA-78，在脂多糖存在的情况下会增加。对关节炎患者或正常受试者滑膜组织中ENA-78的免疫组织化学定位显示，这种趋化因子的主要细胞来源是滑膜衬里细胞，其次是巨噬细胞、内皮细胞和成纤维细胞。与正常滑膜组织相比，RA滑膜组织中的巨噬细胞和成纤维细胞ENA-78免疫阳性更强（P<0.05）。这些结果首次证明了ENA-78在人类疾病状态中的存在，表明ENA-78可能在RA患者发炎关节环境中PMN的募集中起重要作用。
