Takano S, Uchida K, Inoue G, Miyagi M, Aikawa J, Iwase D, Iwabuchi K, Matsumoto T, Satoh M, Mukai M, Minatani A, Takaso M
Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
Department of Immunology, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan.
Clin Exp Immunol. 2017 Nov;190(2):235-243. doi: 10.1111/cei.13007. Epub 2017 Jul 27.
Nerve growth factor (NGF) functions to modulate osteoarthritis (OA)-associated pain. Although recent studies suggest that tumour necrosis factor (TNF)-α and interleukin (IL)-1β mediate NGF activity in human synovial fibroblasts, the regulation of NGF expression in human synovial macrophages remains unclear. Here, we examined the role of macrophages in the production and regulation of synovial (SYN) NGF in osteoarthritic knee joints by examining the mRNA expression of TNF-α and IL-1β in freshly isolated CD14-positive (macrophage-rich fraction) and CD14-negative cells (fibroblast-rich fraction) in synovial tissue from OA patients by quantitative polymerase chain reaction. We also examined the effects of IL-1β and TNF-α on NGF mRNA expression in cultured CD14-positive (macrophage-rich fraction) and CD14-negative cells (fibroblast-rich fraction). In addition, to examine the contribution of macrophages to NGF, TNF-α and IL-1β expression, we injected clodronate liposomes systemically into STR/Ort mice, an osteoarthritis animal model, to deplete macrophages. TNF-α and IL-1β mRNA levels in CD14-positive cells from the SYN of OA patients was significantly higher than that in CD14-negative cells, while NGF expression did not differ markedly between the two cell fractions. In addition, treatment of human cultured CD14-positive and -negative cells with IL-1β and TNF-α enhanced NGF mRNA and protein levels. Expression of NGF, IL-1β and TNF-α was also reduced significantly in STR/Ort mice upon macrophage depletion. These findings suggest that IL-1β and TNF-α regulate NGF expression and production in synovial macrophages and fibroblasts in osteoarthritic joints.
神经生长因子（NGF）具有调节骨关节炎（OA）相关疼痛的功能。尽管最近的研究表明肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β介导人滑膜成纤维细胞中的NGF活性，但人滑膜巨噬细胞中NGF表达的调控仍不清楚。在此，我们通过定量聚合酶链反应检测OA患者滑膜组织中新鲜分离的CD14阳性（富含巨噬细胞部分）和CD14阴性细胞（富含成纤维细胞部分）中TNF-α和IL-1β的mRNA表达，研究巨噬细胞在骨关节炎膝关节滑膜（SYN）NGF产生和调控中的作用。我们还检测了IL-1β和TNF-α对培养的CD14阳性（富含巨噬细胞部分）和CD14阴性细胞（富含成纤维细胞部分）中NGF mRNA表达的影响。此外，为了研究巨噬细胞对NGF、TNF-α和IL-1β表达的贡献，我们将氯膦酸盐脂质体全身注射到骨关节炎动物模型STR/Ort小鼠体内以耗尽巨噬细胞。OA患者SYN中CD14阳性细胞中的TNF-α和IL-1β mRNA水平显著高于CD14阴性细胞，而两种细胞组分之间的NGF表达没有明显差异。此外，用IL-1β和TNF-α处理人培养的CD14阳性和阴性细胞可提高NGF mRNA和蛋白水平。巨噬细胞耗竭后，STR/Ort小鼠中NGF、IL-1β和TNF-α的表达也显著降低。这些发现表明，IL-1β和TNF-α调节骨关节炎关节滑膜巨噬细胞和成纤维细胞中NGF的表达和产生。
