Abundant expression of the interleukin (IL)23 subunit p19, but low levels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll-like receptor-(TLR) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis
Abundant expression of the interleukin (IL)23 subunit p19, but low levels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll-like receptor-(TLR) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis
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DOI：
10.1136/ard.2007.082081
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发表时间：
2009-01-01
影响因子：
27.4
通讯作者：
Kyburz, D.
中科院分区：
文献类型：
--
作者：
Brentano, F.;Ospelt, C.;Kyburz, D.
目的：白细胞介素 (IL)23 由 p19 和 p40 亚基组成，被认为在类风湿性关节炎 (RA) 中发挥关键作用，依赖于产生 IL17 的辅助性 T (Th)17 细胞的促进和增殖。然而，之前对人体组织中IL23表达的研究仅基于p19亚基。我们的目的是研究 RA 与骨关节炎 (OA) 患者中 IL23 亚基 p19 和 p40 的表达和调节。方法：通过原位杂交和免疫组织化学分析滑膜组织中 p19 和 p40 的表达。通过 ELISA 测定 RA 和 OA 滑液和血清中的 IL23。通过实时 PCR 和逆转录酶 (RT)-PCR、蛋白质印迹和功能测定，在 RA 滑膜成纤维细胞 (RASF)、单核细胞和单核细胞衍生的树突细胞 (MDDC) 中确定 Toll 样受体 (TLR) 依赖性诱导 p19、p40 和生物活性 IL23。 结果：p19 亚基在 RA 滑膜组织中大量表达，但在 OA 滑膜组织中不表达。 RASF 在滑膜内层和侵袭部位最显着地表达 p19，但在这些部位未检测到异二聚体 IL23。相应地，在 RA 患者的滑液和血清中未检测到或发现可溶性 IL23 水平非常低。通过体外实验，我们证实TLR激活的RASF表达p19，但不表达p40，与单核细胞相反，单核细胞在TLR刺激后产生IL23。结论：RASF中TLR依赖性诱导p19而不是p40，以及RA患者中p19的丰富表达以及IL23水平低或不可检测，这提供了有力的证据，表明p19不一定表明IL23的存在，正如迄今为止提出的那样。
Objective: Interleukin (IL)23, composed of a p19 and a p40 subunit, is suggested to play key roles in rheumatoid arthritis (RA), dependent on the promotion and proliferation of IL17-producing T helper (Th)17 cells. However, previous studies on IL23 expression in human tissues were based on the p19 subunit only. We aimed to study the expression and regulation of IL23 subunits p19 and p40 in RA compared to patients with osteoarthritis (OA).Methods: The expression of p19 and p40 in synovial tissues was analysed by in situ hybridisation and immunohistochemistry. IL23 in RA and OA synovial fluids and sera was determined by ELISA. Toll-like receptor (TLR)-dependent induction of p19, p40 and bioactive IL23 was determined in RA synovial fibroblasts (RASF), monocytes and monocyte-derived dendritic cells (MDDCs) by real-time PCR and reverse transcriptase (RT)-PCR, Western blot and functional assays.Results: The p19 subunit was abundantly expressed in RA but not in OA synovial tissues. p19 was most prominently expressed by RASF in the synovial lining layer and at the site of invasion, but no heterodimeric IL23 was detected at these sites. Correspondingly, soluble IL23 was not detectable or found at very low levels in synovial fluids and sera of patients with RA. By in vitro experiments, we confirmed that TLR-activated RASF expressed p19 but not p40, in contrast to monocytes, which produced IL23 following TLR stimulation.Conclusion: The TLR-dependent induction of p19 but not p40 in RASF and the abundant expression of p19 along with the low or undetectable levels of IL23 in patients with RA provides strong evidence that p19 does not necessarily indicate the presence of IL23, as has been proposed to date.