类风湿关节炎患者成纤维样滑膜细胞产生的白细胞介素-34 支持破骨细胞生成。

Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis.

机构信息

Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.

出版信息

Arthritis Res Ther. 2012 Jan 20;14(1):R14. doi: 10.1186/ar3693.

INTRODUCTION

Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA.

METHODS

IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and one year after treatment. Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor alpha (TNFα) for 24 hours and used for functional assay.

RESULTS

IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-κB) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with TNFα promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody.

CONCLUSIONS

These data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.

简介

白细胞介素-34（IL-34）是一种新定义的细胞因子，与巨噬细胞集落刺激因子（M-CSF）具有功能重叠。本研究旨在探讨白细胞介素-34（IL-34）在类风湿关节炎（RA）患者中的表达，并研究其在 RA 中的调节和致病作用。

方法

采用免疫组织化学、实时 PCR、酶联免疫吸附试验和免疫印迹法检测 RA 滑膜、滑液（SF）和成纤维样滑膜细胞（FLS）中的 IL-34 水平。采用基线和治疗 1 年后血浆中的疾病活动评分 28（DAS28）评估 RA 活性。用肿瘤坏死因子-α（TNFα）处理 RA FLS 24 小时制备条件培养基（CM），用于功能测定。

结果

IL-34 在 RA 患者的滑膜、SF 和 FLS 中表达。与骨关节炎（OA）患者相比，TNFα可上调 RA 样本中 FLS 中 IL-34 的产生。重要的是，TNFα 在 RAFLS 中优先诱导 IL-34 而不是 M-CSF，这是由转录因子核因子 kappa B（NF-κB）和 c-Jun N 末端激酶（JNK）的激活介导的。RA 患者血浆中 IL-34 的升高在接受疾病修饰抗风湿药物（DMARDs）治疗后降低，与 DAS28 的降低一致。用 TNFα 培养的 RAFLS 的 CM 促进人外周血单核细胞（PBMC）的趋化迁移和随后的破骨细胞（OC）形成，抗 IL-34 抗体可减弱这些作用。