Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis
Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis
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DOI：
10.1002/art.21754
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发表时间：
2006-04-01
影响因子：
--
通讯作者：
Ishigatsubo, Y
中科院分区：
文献类型：
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作者：
Kobayashi, H;Takeno, M;Ishigatsubo, Y
Objective.目的探讨血红素氧合酶1（HO-1）在类风湿关节炎（RA）中的表达及其在RA发病中的作用。采用免疫印迹和免疫组织化学方法检测RA患者、骨关节炎患者和非炎性关节疾病患者滑膜组织中HO-1的表达。采用实时荧光定量PCR和免疫印迹技术分析了血红素（HO-1的化学诱导剂）、HO-1特异性小干扰RNA（siRNA）、HO-1表达载体和抗风湿药物等对RA滑膜细胞系HO-1表达的影响。通过实时荧光PCR和酶联免疫吸附试验检测细胞因子的合成。HO-1在RA患者滑膜组织中的表达明显高于其他患者组。血红素、金诺芬和HO-1表达载体诱导HO-1并降低滑膜细胞系中肿瘤坏死因子α（TNF α）信使RNA的表达、脂多糖（LPS）诱导的白细胞介素-6（IL-6）和IL-8的分泌以及环氧化酶2的表达。用HO-1特异性siRNA处理增加了TNF α、IL-6和IL-8的合成，并取消了金诺芬对TNF α分泌的抑制作用。当将血红蛋白作为一氧化碳的清除剂加入到经金雀花甙处理的滑膜细胞系中时，LPS依赖的IL-6和IL-8的产生增加。我们的数据表明，HO-1在RA滑膜组织中表达，并在炎症的发展中起着调节作用。金诺芬的药理作用部分取决于HO-1的水平，这表明HO-1诱导是RA的一种新的治疗策略。
Objective. To examine the expression and pathogenetic roles of heme oxygenase 1 (HO-1), an inducible heme-degrading enzyme with antiinflammatory properties, in rheumatoid arthritis (RA).Methods. HO-1 expression in synovial tissue from patients with RA, patients with osteoarthritis, and patients with noninflammatory joint diseases was determined by immunoblotting and immunohistochemistry. Effects of various agents, such as hemin (a chemical inducer of HO-1), small interfering RNA (siRNA) specific for HO-1, HO-1 expression vector, and antirheumatic agents, on HO-1 expression in RA synovial cell lines were analyzed by real-time reverse transcription-polymerase chain reaction (PCR) and immunoblotting. Cytokine synthesis was evaluated by real-time PCR and enzyme-linked immunosorbent assay.Results. HO-1 was expressed more abundantly in the lesions of synovial tissue from patients with RA than in those from the other patient groups. Hemin, auranofin, and HO-1 expression vector induced HO-1 and reduced expression of tumor necrosis factor alpha (TNF alpha) messenger RNA, lipopolysaccharide (LPS)-induced secretion of interleukin-6 (IL-6) and IL-8, and expression of cyclooxygenase 2 in the synovial cell lines. Treatment with HO-1-specific siRNA augmented the synthesis of TNF alpha, IL-6, and IL-8 and canceled the suppressive effects of auranofin on TNF alpha secretion. When hemoglobin, as a scavenger of carbon monoxide, was added to auranofin-treated synovial cell lines, LPS-dependent production of IL-6 and IL-8 was increased.Conclusion. Our data demonstrate that HO-1 is expressed in RA synovial tissues and plays a regulatory role in the development of inflammation. The pharmacologic effects of auranofin depend, in part, on the levels of HO-1, suggesting that HO-1 induction is a novel therapeutic strategy for RA.