Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures
Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures
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DOI：
10.4049/jimmunol.181.11.8002
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发表时间：
2008-12-01
影响因子：
4.4
通讯作者：
Foxwell, Brian M.
中科院分区：
文献类型：
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作者：
Sacre, Sandra M.;Lo, Alexandra;Foxwell, Brian M.
抗TNF生物制剂的出现是类风湿性关节炎（RA）治疗的一个开创性进展，并证实了TNF在疾病发病机制中的重要作用。然而，目前还不清楚是什么维持了TNF的慢性产生。在这项研究中，我们研究了米安色林，一种5-羟色胺受体拮抗剂的抗炎特性。我们发现米安色林能够抑制原代人细胞中的内体TLR 3、7、8和9，并抑制RA滑膜培养物中TNF和IL-6的自发释放。这表明这些TLR在RA产生TNF和IL-6中的作用，这得到了氯喹的数据的支持，氯喹是一种内体酸化抑制剂（TLR 3、7、8和9活化的先决条件），也抑制了RA滑膜培养物产生这些细胞因子。仅TLR 3或8的刺激从这些培养物诱导TNF，表明TLR 7和TLR 9在该模型中的影响较小。表明TLR 8重要性的关键观察结果是咪喹莫特对自发TNF产生的抑制，我们发现咪喹莫特是TLR 8的抑制剂。总之，这些数据表明，TLR 8可能在驱动RA中的TNF产生中发挥作用。因为这种受体可以被小分子量的分子，它可能被证明是一个重要的治疗靶点。免疫学杂志，2008，181：8002-8009。
The advent of anti-TNF biologicals has been a seminal advance in the treatment of rheumatoid arthritis (RA) and has confirmed the important role of TNF in disease pathogenesis. However, it is unknown what sustains the chronic production of TNF. In this study, we have investigated the anti-inflammatory properties of mianserin, a serotonin receptor antagonist. We discovered mianserin was able to inhibit the endosomal TLRs 3, 7, 8, and 9 in primary human cells and inhibited the spontaneous release of TNF and IL-6 from RA synovial membrane cultures. This suggested a role for these TLRs in production of TNF and IL-6 from RA which was supported by data from chloroquine, an inhibitor of endosomal acidification (a prerequisite for TLRs 3, 7, 8, and 9 activation) which also inhibited production of these cytokines from RA synovial cultures. Only stimulation of TLR 3 or 8 induced TNF from these cultures, indicating that TLR7 and TLR9 were of less consequence in this model. The key observation that indicated the importance of TLR8 was the inhibition of spontaneous TNF production by imiquimod, which we discovered to be an inhibitor of TLR8. Together, these data suggest that TLR8 may play a role in driving TNF production in RA. Because this receptor can be inhibited by small m.w. molecules, it may prove to be an important therapeutic target. The Journal of Immunology, 2008, 181: 8002-8009.