IL-40 is a novel cytokine associated with autoimmune connective tissue disorders such as rheumatoid arthritis (RA) or Sjögren syndrome. We have previously shown an accumulation of IL-40 in the RA joint and its expression by immune cells and fibroblasts. Therefore, we aimed to assess the role of IL-40 in association with hyaline cartilage and chondrocyte activity. Immunohistochemistry was employed to detect IL-40 in paired samples of loaded and unloaded regions of osteoarthritis (OA) cartilage (n=5). Synovial fluid IL-40 was analysed by ELISA in OA (n=31) and control individuals after knee injury (n=34). The impact of IL-40 on chondrocytes was tested in vitro. IL-40 was found in chondrocytes of the superficial zone of the OA cartilage, both in loaded and unloaded explants. Additionally, only biopsies from loaded explants showed significant IL-40 positivity in transitional zone chondrocytes. Levels of IL-40 were significantly elevated in the synovial fluid from OA patients compared to controls (p<0.0009) and correlated with synovial fluid leukocyte counts in OA (r=0.444, p=0.014). Chondrocytes exposed to IL-40 dose dependently increased in the secretion of pro-inflammatory cytokines IL-6 (p<0.0001) and IL-8 (p=0.004). Moreover, a dose dependent up-regulation of matrix degrading metalloproteinases MMP-1 (p=0.004), MMP-3 (p=0.031) and MMP-13 (p=0.0002) upon IL-40 treatment was observed in contrast to untreated chondrocytes. This study is the first to demonstrate the accumulation of IL-40 in OA cartilage and its up-regulation in the synovial fluid of OA patients compared to controls. In addition, extracellular IL-40 appears to play a role in promoting inflammation and cartilage destruction by driving chondrocyte behaviour towards a more aggressive phenotype.

中文翻译：

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IL-40 在骨关节炎患者的滑液和软骨中表达上调，并有助于体外软骨细胞表型的改变


IL-40 是一种新型细胞因子，与类风湿性关节炎 (RA) 或干燥​​综合征等自身免疫性结缔组织疾病相关。我们之前已经展示了 RA 关节中 IL-40 的积累及其通过免疫细胞和成纤维细胞的表达。因此，我们的目的是评估 IL-40 在透明软骨和软骨细胞活性中的作用。采用免疫组织化学方法检测骨关节炎 (OA) 软骨加载和卸载区域的配对样本中的 IL-40 (n=5)。通过 ELISA 分析 OA (n=31) 和膝关节损伤后对照个体 (n=34) 的滑液 IL-40。体外测试了 IL-40 对软骨细胞的影响。在负载和未负载的外植体中，在 OA 软骨浅表区的软骨细胞中发现了 IL-40。此外，仅来自加载的外植体的活检显示移行区软骨细胞中显着的 IL-40 阳性。与对照组相比，OA 患者滑液中的 IL-40 水平显着升高（p<0.0009），并且与 OA 滑液白细胞计数相关（r=0.444，p=0.014）。暴露于 IL-40 的软骨细胞促炎细胞因子 IL-6 (p<0.0001) 和 IL-8 (p=0.004) 的分泌呈剂量依赖性增加。此外，与未处理的软骨细胞相比，在 IL-40 处理后观察到基质降解金属蛋白酶 MMP-1 (p=0.004)、MMP-3 (p=0.031) 和 MMP-13 (p=0.0002) 的剂量依赖性上调。这项研究首次证明了 OA 软骨中 IL-40 的积累及其在 OA 患者滑液中与对照组相比的上调。此外，细胞外 IL-40 似乎通过驱动软骨细胞行为向更具攻击性的表型发挥促进炎症和软骨破坏的作用。