Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes.
Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes.
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DOI：
10.1136/annrheumdis-2011-201203
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发表时间：
2013-03
影响因子：
27.4
通讯作者：
Shahrara S
中科院分区：
文献类型：
--
作者：
Chamberlain ND;Kim SJ;Vila OM;Volin MV;Volkov S;Pope RM;Arami S;Mandelin AM 2nd;Shahrara S
本研究旨在探讨TLR7和TLR8在类风湿关节炎(RA)中的表达、调控及其致病作用。用免疫组织化学方法检测TLR7和TLR8在RA、骨关节炎(OA)和正常滑膜组织(ST)中的表达。接下来，我们通过Western印迹分析和ELISA法研究了TLR7和TLR8结扎介导促炎反应的机制。RA患者单核细胞TLR7、TLR8的表达与疾病活动评分(DAS28)、肿瘤坏死因子-α水平相关。进一步研究TLR7结扎对滑液介导的肿瘤坏死因子α转录的影响。TLR7/TLR8主要表达于RA ST衬里和衬里下层巨噬细胞。我们发现，在RA外周血(PB)分化的巨噬细胞中，NF-κB和/或PI3K通路在TLR7/TLR8诱导炎性因子方面是必不可少的。TLR7在RA单核细胞中的表达与DAS28、肿瘤坏死因子-α水平呈正相关。相反，TLR8在这些细胞中的表达与DAS28、TLR7或肿瘤坏死因子-α水平无关。我们进一步证明，来自RA SF而不是RA或NL血浆的RNA可以调节RA单核细胞的肿瘤坏死因子α转录，这种转录可以通过拮抗TLR7的连接或单链RNA的降解而下调。因此，RA SF中存在的单链RNA可能是TLR7的潜在内源性配体。这些结果提示TLR7的表达而不是TLR8的表达可能是RA疾病活动性和抗肿瘤坏死因子-α应答的预测因子，靶向TLR7可能抑制RA的慢性进展。
The aim of the study was to characterize the expression, regulation and pathogenic role of TLR7 and TLR8 in rheumatoid arthritis (RA). Expression of TLR7 and TLR8 was demonstrated in RA, osteoarthritis (OA) and normal (NL) synovial tissues (ST) employing immunohistochemistry. We next examined the mechanism by which TLR7 and TLR8 ligation mediates proinflammatory response by Western blot analysis and ELISA. Expression of TLR7 and TLR8 in RA monocytes was correlated to disease activity score (DAS28) and TNF-α levels. Further the effect of TLR7 ligation in RA monocytes was determined on synovial fluid (SF) mediated TNF-α transcription. TLR7/TLR8 are predominately expressed in RA ST lining and sublining macrophages. We show that NF-κB and/or PI3K pathways are essential for TLR7/TLR8 induction of proinflammatory factors in RA peripheral blood (PB) differentiated macrophages. Expression of TLR7 in RA monocytes shows a strong correlation with DAS28 and TNF-α levels. In contrast, expression of TLR8 in these cells does not correlate with DAS28, TLR7 or TNF-α levels. We further demonstrate that RNA from RA SF but not RA or NL plasma could modulate TNF-α transcription from RA monocytes that can be downregulated by antagonizing TLR7 ligation or degradation of single stand (ss) RNA. Thus, ssRNA present in RA SF may function as a potential endogenous ligand for TLR7. These results suggest that expression of TLR7 but not TLR8 may be a predictor for RA disease activity and anti-TNF-α responsiveness, and targeting TLR7 may suppress chronic progression of RA.
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影响因子：
4.4
作者：
Sacre, Sandra M.;Lo, Alexandra;Foxwell, Brian M.
通讯作者：
Foxwell, Brian M.
影响因子：
--
作者：
Pickens, Sarah R.;Chamberlain, Nathan D.;Volin, Michael V.;Pope, Richard M.;Talarico, Nicholas E.;Mandelin, Arthur M., II;Shahrara, Shiva
通讯作者：
Shahrara, Shiva
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
15.9
作者：
Abdollahi-Roodsaz, Shahla;Joosten, Leo A. B.;Van den Berg, Wim B.
通讯作者：
Van den Berg, Wim B.
影响因子：
3.6
作者：
Makela, Sanna M.;Osterlund, Pamela;Julkunen, Ilkka
通讯作者：
Julkunen, Ilkka