Shahrara Shiva, Park Christy C, Temkin Vladislav, Jarvis Jared W, Volin Michael V, Pope Richard M
Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
J Immunol. 2006 Oct 15;177(8):5077-87. doi: 10.4049/jimmunol.177.8.5077.
Monocytes are the key regulators of joint inflammation and destruction in rheumatoid arthritis; hence, suppression of their recruitment into the joint may be therapeutically beneficial. Chemokines, including RANTES, are highly expressed in the joints of patient with rheumatoid arthritis, and they promote leukocyte trafficking into the synovial tissue. Because endogenous TLR4 ligands are expressed in the rheumatoid joint, the TLR4 ligand LPS was used to characterize the effects of RANTES on the TLR4-mediated induction of TNF-alpha and IL-6. Using peripheral blood (PB) monocytes, RANTES decreased LPS-induced IL-6 transcriptionally, whereas TNF-alpha was suppressed at the posttranscriptional level. RANTES signaled through p38 MAPK, and this signaling was further enhanced by LPS stimulation in PB monocytes, resulting in the earlier and increased secretion of IL-10. Inhibition of p38 by short-interfering RNA or a chemical inhibitor, as well as neutralization of IL-10, reversed the RANTES-mediated suppression of LPS-induced IL-6 and TNF-alpha. Further, when rheumatoid arthritis synovial fluid was added to PB monocytes, the neutralization of RANTES in fluid reduced the LPS-induced IL-10 and increased TNF-alpha. In conclusion, the results of this study suggest that RANTES down-regulates TLR4 ligation-induced IL-6 and TNF-alpha secretion by enhancing IL-10 production in PB monocytes. These observations suggest that the therapeutic neutralization of RANTES, in addition to decreasing the trafficking of leukocytes, may have a proinflammatory effect at the site of established chronic inflammation.
单核细胞是类风湿性关节炎中关节炎症和破坏的关键调节因子；因此，抑制它们募集到关节中可能具有治疗益处。趋化因子，包括RANTES，在类风湿性关节炎患者的关节中高度表达，并且它们促进白细胞向滑膜组织的迁移。由于内源性TLR4配体在类风湿关节中表达，因此使用TLR4配体LPS来表征RANTES对TLR4介导的TNF-α和IL-6诱导的影响。使用外周血（PB）单核细胞，RANTES在转录水平上降低LPS诱导的IL-6，而TNF-α在转录后水平受到抑制。RANTES通过p38 MAPK发出信号，并且在PB单核细胞中LPS刺激进一步增强了该信号传导，导致IL-10的更早和更多分泌。通过短干扰RNA或化学抑制剂抑制p38，以及中和IL-10，可逆转RANTES介导的对LPS诱导的IL-6和TNF-α的抑制。此外，当将类风湿性关节炎滑液添加到PB单核细胞中时，中和滑液中的RANTES可降低LPS诱导的IL-10并增加TNF-α。总之，本研究结果表明，RANTES通过增强PB单核细胞中IL-10的产生来下调TLR4连接诱导的IL-6和TNF-α分泌。这些观察结果表明，RANTES的治疗性中和除了减少白细胞迁移外，可能在已建立的慢性炎症部位具有促炎作用。
