Ikeuchi Hidekazu, Kuroiwa Takashi, Hiramatsu Noriyuki, Kaneko Yoriaki, Hiromura Keiju, Ueki Kazue, Nojima Yoshihisa
Gunma University Graduate School of Medicine, Maebashi, Japan.
Arthritis Rheum. 2005 Apr;52(4):1037-46. doi: 10.1002/art.20965.
Interleukin-22 (IL-22) is a novel cytokine of the IL-10 family. Although its pathophysiologic function is largely unknown, induction of acute-phase responses by IL-22 has suggested proinflammatory properties. In this study, we sought to examine whether IL-22 plays a role in the pathogenesis of rheumatoid arthritis (RA).
Expression of IL-22 and IL-22 receptor 1 (IL-22R1) was examined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis. The effects of recombinant IL-22 (rIL-22) on cultured synovial fibroblasts derived from RA patients (RASF), with regard to the proliferation of synovial fibroblasts and production of monocyte chemoattractant protein 1 (MCP-1), were examined by alamer blue assay and enzyme-linked immunosorbent assay, respectively.
IL-22 messenger RNA was detected by RT-PCR in RA synovial tissues and mononuclear cells isolated from RA synovial fluid samples. High levels of IL-22 were expressed both in the lining and the sublining layers of RA synovial tissues. Staining for vimentin and CD68, as markers of synovial fibroblasts and macrophages, respectively, showed that the majority of IL-22-positive cells were synovial fibroblasts and macrophages. IL-22R1 was also expressed in both the lining and the sublining layers of RA synovial tissues. The majority of cells expressing IL-22R1 were positive for vimentin, but not for CD68. Expression of IL-22 and IL-22R1 in RASF was confirmed by RT-PCR and Western blot analysis. In vitro, rIL-22 significantly increased proliferation of RASF and production of MCP-1 by RASF above the value of medium controls. Moreover, MAPK activation was induced in RASF in response to IL-22 stimulation.
These data suggest that IL-22, produced by synovial fibroblasts and macrophages, promotes inflammatory responses in RA synovial tissues by inducing the proliferation and chemokine production of synovial fibroblasts.
白细胞介素-22（IL-22）是白细胞介素-10家族的一种新型细胞因子。尽管其病理生理功能在很大程度上尚不清楚，但IL-22诱导急性期反应提示其具有促炎特性。在本研究中，我们试图探讨IL-22在类风湿关节炎（RA）发病机制中是否起作用。
采用逆转录-聚合酶链反应（RT-PCR）、蛋白质印迹法和免疫组织化学分析检测IL-22和IL-22受体1（IL-22R1）的表达。分别通过alamar蓝检测法和酶联免疫吸附测定法，检测重组IL-22（rIL-22）对来源于RA患者的培养滑膜成纤维细胞（RASF）的影响，包括滑膜成纤维细胞的增殖和单核细胞趋化蛋白1（MCP-1）的产生。
通过RT-PCR在RA滑膜组织和从RA滑膜液样本中分离出的单核细胞中检测到IL-22信使核糖核酸。在RA滑膜组织的衬里层和衬里下层均表达高水平的IL-22。波形蛋白和CD68染色分别作为滑膜成纤维细胞和巨噬细胞的标志物，显示大多数IL-22阳性细胞为滑膜成纤维细胞和巨噬细胞。IL-22R1在RA滑膜组织的衬里层和衬里下层也有表达。大多数表达IL-22R1的细胞波形蛋白呈阳性，但CD68呈阴性。通过RT-PCR和蛋白质印迹分析证实了RASF中IL-22和IL-22R1的表达。在体外，rIL-22显著增加RASF的增殖以及RASF产生的MCP-1，其水平高于培养基对照值。此外，IL-22刺激可诱导RASF中的丝裂原活化蛋白激酶（MAPK）激活。
这些数据表明，由滑膜成纤维细胞和巨噬细胞产生的IL-22通过诱导滑膜成纤维细胞的增殖和趋化因子产生，促进RA滑膜组织中的炎症反应。
