Morita Y, Yamamura M, Nishida K, Harada S, Okamoto H, Inoue H, Ohmoto Y, Modlin R L, Makino H
Okayama University Medical School, Japan.
Arthritis Rheum. 1998 Feb;41(2):306-14. doi: 10.1002/1529-0131(199802)41:2<306::AID-ART15>3.0.CO;2-4.
To examine the importance of interleukin-12 (IL-12) as a factor in the interferon-gamma (IFNgamma)-dominant T cell cytokine response in the synovial tissue of patients with rheumatoid arthritis (RA).
The expression of IL-12 in synovial tissue samples from patients with chronic RA (> or = 2 years) was compared with that in samples from osteoarthritis (OA) patients by detection of IL-12 p40 messenger RNA (mRNA) using reverse transcriptase-polymerase chain reaction, measurement of IL-12 p70 protein in culture supernatants of tissue cells by immunoassay, and immunostaining of tissue sections with anti-IL-12 p70. The production of IFNgamma by RA synovial tissue cells cultured with or without IL-12 was determined. In addition, T cells were obtained 14 days after culturing RA synovial tissue cells with IL-2 alone or with IL-2 plus IL-12, neutralizing anti-IL-12, or IL-4, and cytokine patterns (i.e., IFNgamma and IL-4 levels) were determined by stimulating cells for 24 hours with anti-CD3 plus phorbol myristate acetate.
Synovial tissues from RA patients more strongly expressed IL-12 p40 mRNA than did OA tissues. Dissociated tissue cells from 21 of 37 RA patients spontaneously released detectable amounts of IL-12 p70 (> or = 12.5 pg/ml) in culture, whereas production of IL-12 by OA tissues was limited. By immunohistochemical analysis, IL-12-producing cells were localized mainly in the sublining layer of RA synovium, and mostly expressed the CD68 antigen. Levels of IFNgamma production by RA synovial tissue cells were potently and selectively enhanced by IL-12. The ability of IL-2-expanding synovial T cells to produce IFNgamma was augmented by costimulation with IL-12 and diminished by anti-IL-12, while it was not affected by IL-4.
These data suggest that IL-12, produced mainly by macrophage-lineage cells, may be involved in IFNgamma-dominant cytokine production by infiltrating T cells in joints with chronic RA.
探讨白细胞介素-12（IL-12）作为类风湿关节炎（RA）患者滑膜组织中γ干扰素（IFNγ）主导的T细胞细胞因子反应相关因子的重要性。
通过逆转录聚合酶链反应检测IL-12 p40信使核糖核酸（mRNA）、用免疫分析法测定组织细胞培养上清液中的IL-12 p70蛋白以及用抗IL-12 p70对组织切片进行免疫染色，比较慢性RA（≥2年）患者滑膜组织样本与骨关节炎（OA）患者样本中IL-12的表达情况。测定在有或无IL-12情况下培养的RA滑膜组织细胞产生IFNγ的情况。此外，在用IL-2单独培养或用IL-2加IL-12、中和性抗IL-12或IL-4培养RA滑膜组织细胞14天后获取T细胞，并用抗CD3加佛波酯肉豆蔻酸酯刺激细胞24小时，测定细胞因子模式（即IFNγ和IL-4水平）。
RA患者的滑膜组织比OA组织更强烈地表达IL-12 p40 mRNA。37例RA患者中有21例的解离组织细胞在培养中自发释放可检测量的IL-12 p70（≥12.5 pg/ml），而OA组织产生IL-12的量有限。通过免疫组织化学分析，产生IL-12的细胞主要定位于RA滑膜的衬里下层，且大多表达CD68抗原。IL-12可有效且选择性地增强RA滑膜组织细胞产生IFNγ的水平。IL-2扩增的滑膜T细胞产生IFNγ的能力在与IL-12共刺激时增强，在使用抗IL-12时减弱，而不受IL-4影响。
这些数据表明，主要由巨噬细胞系细胞产生的IL-12可能参与慢性RA关节中浸润T细胞产生的以IFNγ为主的细胞因子生成过程。
