Study on the mechanism for the production of CXCR3-agonisitic chemokines by synovial fibroblasts from patients with rheumatoid arthritis

类风湿关节炎滑膜成纤维细胞产生CXCR3激动趋化因子的机制研究

• 批准号: 14570413
• 负责人: YAMAMURA Masahiro
• 金额: $ 2.24万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570413/
• 关键词: rheumatoid arthritis; Th1-immune response; synovial fibroblasts; CXCL9 (Mig); CXCL10 (IP-10); CXCL11 (1-TAC); interferon-γ (IFN-γ); tumor necrosis factor-α (TNF-α); CXCR3リガンド; インターフェロンγ(IFN-γ); STAT1; NF-κB; CXCR3; Mig(CXCL9); IP-10(CXCL10)

The inflamed synovial tissue of rheumatoid arthritis (RA) is characterized by an infiltration with Th1 cells that predominantly express the chemokine receptors CXCR3 and CCRS. In this study, we investigated the production of the CXCR3 agonistic chemokines CXCL9, CXCL10, and CXCL11 by synovial tissue cells and synovial fibroblast-cell lines (forth or fifth passage) from RA patients. Concentrations of all CXCR3 ligands in synovial fluids were markedly higher in RA patients than in osteoarthritis (OA) patients. Synovial tissue cells from RA patients more strongly expressed mRNAs for CXCR3 ligands and spontaneously secreted larger amounts of these chemokine proteins, compared with the cells from OA patients. The mRNA expression of all CXCR3 ligands was induced in synovial fibroblasts from RA patients after stimulation with interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). However, synovial fibroblasts significantly secreted CXCL9 and CXCL10 proteins, but not CXCL11 protein, after IFN-γ stimulation, and secreted only CXCL10 protein after TNF-α or IL-1β stimulation. When stimulated with a combination of IFN-γ and TNF-α, these cells were able to secrete large amounts of all three chemokines. These results indicate that synovial fibroblasts may be involved in perpetuating the Th1 immune response by producing the Th1-associated chemokines CXCR3 ligands, and the synergistic effect of IFN-γ and TNF-α may be important for their chemokine production in RA joints.

类风湿性关节炎（RA）的发炎滑膜组织的特征在于主要表达趋化因子受体CXCR 3和CCRS的Th 1细胞的浸润。在这项研究中，我们研究了类风湿关节炎患者滑膜组织细胞和滑膜成纤维细胞系（第四代或第五代）产生的CXCR 3激动性趋化因子CXCL 9，CXCL 10和CXCL 11。RA患者滑液中所有CXCR 3配体的浓度明显高于骨关节炎（OA）患者。与OA患者的细胞相比，RA患者的滑膜组织细胞更强烈地表达CXCR 3配体的mRNA，并自发分泌更大量的这些趋化因子蛋白。用干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）或白细胞介素-1 β（IL-1β）刺激RA患者滑膜成纤维细胞后，诱导所有CXCR 3配体的mRNA表达。然而，滑膜成纤维细胞在IFN-γ刺激后显著分泌CXCL 9和CXCL 10蛋白，但不分泌CXCL 11蛋白，并且在TNF-α或IL-1β刺激后仅分泌CXCL 10蛋白。当用IFN-γ和TNF-α联合刺激时，这些细胞能够分泌大量的所有三种趋化因子。这些结果表明滑膜成纤维细胞可能通过产生Th 1相关趋化因子CXCR 3配体参与维持Th 1免疫应答，并且IFN-γ和TNF-α的协同作用可能对RA关节中趋化因子的产生很重要。

项目成果

Bleharski JR, Li H, Meinken C, Graeber TG, Ochoa M-T, Yamamura M, Burdick A, Sarno EN, Wagner M, Rollinghoff M, Rea TH, Colonna M, Stenger S, Bloom BR, Eisenberg D, Modlin RL: "Use of genomic profiling in leprosy to discriminate clinical forms of the dise

Bleharski JR、Li H、Meinken C、Graeber TG、Ochoa M-T、Yamamura M、Burdick A、Sarno EN、Wagner M、Rollinghoff M、Rea TH、Colonna M、Stenger S、Bloom BR、Eisenberg D、Modlin RL：“使用

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Aita T, Yamamura M, Kawashima M, Okamoto A, Iwahashi M, Yamana M, Makino M: "Expression of interleukin-12 receptor (IL-12R) and IL-18R on CD4+ T cells from patients with rheumatoid arthritis."J Rheumatol. 31(3). 448-456 (2004)

Aita T、Yamamura M、Kawashima M、Okamoto A、Iwahashi M、Yamana M、Makino M：“类风湿关节炎患者 CD4 T 细胞上白细胞介素 12 受体 (IL-12R) 和 IL-18R 的表达。”J Rheumatol

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Bleharski JR, Li H, Meinken C, Graeber TG, Ochoa M-T, Yamamura M, et al.: "Use of genomic profiling in leprosy to discriminate clinical forms of the disease."Science. 301・5639. 1527-1530 (2003)

Bleharski JR、Li H、Meinken C、Graeber TG、Ochoa M-T、Yamamura M 等人：“利用麻风病的基因组分析来区分该疾病的临床形式。”《科学》301·5639。