类风湿性关节炎患者膝关节滑膜组织中白细胞介素-18表达与白细胞介素-1β及肿瘤坏死因子α水平升高的相关性

Association of interleukin-18 expression with enhanced levels of both interleukin-1beta and tumor necrosis factor alpha in knee synovial tissue of patients with rheumatoid arthritis.

作者信息

Joosten Leo A B, Radstake Timothy R D, Lubberts Erik, van den Bersselaar Liduine A M, van Riel Piet L C M, van Lent Peter L E M, Barrera Pilar, van den Berg Wim B

机构信息

Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands.

出版信息

Arthritis Rheum. 2003 Feb;48(2):339-47. doi: 10.1002/art.10814.

DOI:10.1002/art.10814

PMID:12571842

Abstract

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, CD14, 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 TNFalpha.

摘要

目的

研究白细胞介素-18（IL-18）在类风湿关节炎（RA）患者滑膜活检组织中的表达模式，并确定这种主要细胞因子的表达是否与其他细胞因子和黏附分子的表达相关，以及是否与关节炎症程度相关。

方法

从29例活动期RA患者获取膝关节滑膜组织活检标本，其中无滑膜炎的标本6例，中度或重度滑膜炎的标本分别为11例和12例。石蜡包埋、速冻切片用于IL-18、肿瘤坏死因子α（TNFα）、IL-1β、IL-12和IL-17的免疫组化检测。此外，对细胞间黏附分子1、血管细胞黏附分子1和E-选择素等黏附分子以及细胞标志物CD3、CD14和CD68进行染色。

结果

80%的RA患者膝关节滑膜组织的衬里层和衬里下层均可检测到IL-18染色。滑膜组织中IL-18的表达与IL-1β的表达密切相关（在衬里下层r = 0.72，在衬里层r = 0.71；均P < 0.0001）以及与TNFα的表达密切相关（在衬里下层r = 0.59，P < 0.0007，在衬里层r = 0.68，P < 0.0001）。此外，衬里下层中IL-18的表达与巨噬细胞浸润相关（r = 0.64，P < 0.0007）和显微镜下炎症评分相关（r = 0.78，P < 0.0001），并与红细胞沉降率所测量的急性期反应相关（r = 0.61，P < 0.0004）。有趣的是，共表达IL-18和IL-12的RA滑膜组织显示Th1相关细胞因子IL-17水平升高。