Association of interleukin-18 expression with enhanced levels of both interleukin-1β and tumor necrosis factor α in knee synovial tissue of patients with rheumatoid arthritis
Association of interleukin-18 expression with enhanced levels of both interleukin-1β and tumor necrosis factor α in knee synovial tissue of patients with rheumatoid arthritis
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DOI：
10.1002/art.10814
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发表时间：
2003-02-01
影响因子：
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通讯作者：
van den Berg, WB
中科院分区：
文献类型：
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作者：
Joosten, LAB;Radstake, TRD;van den Berg, WB
Objective.检测类风湿关节炎（RA）患者滑膜活检组织中白细胞介素18（IL-18）的表达模式，并确定这种主要细胞因子的表达是否与其他细胞因子和粘附分子的表达相关，以及与关节炎症程度相关。从29例活动性RA患者中获得膝关节滑膜组织活检标本，无滑膜炎（n = 6）或中度或重度滑膜炎（分别为n = 11和n = 12）。石蜡包埋、速冻切片用于IL-18、肿瘤坏死因子α（TNF α）、IL-1 β、IL-12和IL-17的免疫组织化学检测。此外，还对细胞间粘附分子1、血管细胞粘附分子1和E-选择素等粘附分子以及细胞标志物CD 3、CDA 14和CD 68进行了染色。在80%的RA患者中，膝关节滑膜组织的衬里和衬里下均可检测到IL-18染色。滑膜组织中IL-18的表达与IL-1 β（衬里下层r = 0.72，衬里层r = 0.71;均P < 0.0001）和TNF α（衬里下层r = 0.59，P < 0.0007，衬里层r = 0.68，P < 0.0001）的表达密切相关。此外，白细胞介素18表达与巨噬细胞浸润（r = 0.64，P < 0.0007）和显微镜下炎症评分（r = 0.78，P < 0.0001）以及红细胞沉降率测定的急性期反应（r = 0.61，P < 0.0004）相关。有趣的是，RA滑膜组织中共表达IL-18和IL-12的Th 1相关细胞因子IL-17水平升高。我们的研究结果表明，IL-18的表达与IL-1 β和TNF α的表达以及RA患者滑膜组织中的局部炎症相关。此外，滑膜IL-18表达与急性期反应相关。这些数据表明，IL-18是RA中驱动IL-1 β和TNF α局部产生的主要促炎细胞因子。
Objective. To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation.Methods. Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CDA14, and CD68 were stained.Results. IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1beta (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNFalpha (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17.Conclusion. Our results show that expression of IL-18 is associated with that of IL-1beta and TNFalpha and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1beta and TNFa.