Toll-like receptor 2 and 4 combination engagement upregulate IL 15 synergistically in human rheumatoid synovial fibroblasts
Toll-like receptor 2 and 4 combination engagement upregulate IL 15 synergistically in human rheumatoid synovial fibroblasts
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DOI：
10.1016/j.imlet.2006.12.006
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Kim, Ho-Youn
中科院分区：
文献类型：
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作者：
Jung, Young Ok;Cho, Mi-La;Kim, Ho-Youn
Toll 样受体 (TLR) 是连接先天免疫和适应性免疫的模式识别受体。白介素 15 (IL-15) 是一种促炎性先天反应细胞因子，可介导类风湿性关节炎 (RA) 炎症性滑膜炎的多效性效应功能。本研究的目的是阐明 TLR2 和 TLR4 的特异性配体刺激是否会诱导 RA 患者的成纤维样滑膜细胞 (FLS) 产生 IL-15。从 RA 滑膜组织中分离出 FLS，并用 TLR2 配体细菌肽聚糖 (PGN) 和 TLR4 配体脂多糖 (LPS) 进行刺激。通过ELISA测定培养物上清液中的IL-15，并通过RT-PCR和实时PCR评估mRNA水平。通过免疫组织化学对 RA 滑膜中 TLR2、TLR4 和 IL-15 的表达进行定量，并与骨关节炎滑膜中获得的值进行比较。用 PGN 或 PGN 加 LPS 刺激的 RA FLS 培养物上清液中 IL-15 的产生增加，并且在转录水平上上调。相比之下，LPS 并没有增加 IL-15 的水平，尽管它增强了 PGN 对 IL-15 产生的刺激作用。用特定抑制剂抑制核因子 (NF)-κ B 可消除 PGN 或 PGN 加 LPS 对 IL-15 的刺激作用。用阻断性单克隆抗体中和 TLR2 显着降低了 IL-15 的产生 (P < 0.05)，反映了 TLR2 激活在诱导 IL-15 产生中的功能相关性。这些数据表明，微生物成分在 RA FLS 中激活 TLR2 参与了 IL-15 的诱导，并且 TLR2 通过 NF-κ B 促进炎症。TLR4 增强了 TLR2 对 IL-15 的刺激作用，可能有助于 RA 患者滑膜炎的维持。 (c) 2007 Elsevier B.V. 保留所有权利。
Toll-like receptors (TLRs) are pattern-recognition receptors that connect innate and adaptive immunity. Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector functions in inflammatory synovitis of rheumatoid arthritis (RA). The aim of this study was to clarify whether stimulation of TLR2 and TLR4 by their specific ligands induces the production of IL-15 in fibroblast-like synoviocytes (FLS) from RA patients. FLS were isolated from RA synovial tissues and stimulated with the TLR2 ligand bacterial peptidoglycan (PGN) and the TLR4 ligand lipopolysaccharide (LPS). IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real time PCR. The expression of TLR2, TLR4, and IL-15 in the RA synovium was quantified by immunohistochemistry and compared with values obtained in osteoarthritis synovium. IL-15 production increased in culture supernatants of RA FLS stimulated with PGN or PGN plus LPS, and this was upregulated at the transcriptional level. In contrast, LPS did not increase the level of IL-15 although it augmented the stimulatory effect of PGN on IL-15 production. Inhibition of nuclear factor (NF)-kappa B with a specific inhibitor abrogated the stimulatory effect of PGN or PGN plus LPS on IL-15. Neutralization of TLR2 with a blocking monoclonal antibody significantly reduced IL-15 production (P < 0.05), reflecting the functional relevance of TLR2 activation in the induction of IL-15 production. These data suggest that TLR2 activation in RA FLS by microbial constituents is involved in the induction of IL-15 and that TLR2 promotes inflammation through NF-kappa B. TLR4 augmented the stimulatory effect of TLR2 on IL-15, possibly contributing to the maintenance of synovitis in patients with RA. (c) 2007 Elsevier B.V. All rights reserved.