Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice.
Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice.
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DOI：
10.1002/eji.201445174
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发表时间：
2015-03
影响因子：
5.4
通讯作者：
Kang, Young Jun
中科院分区：
文献类型：
--
作者：
Bang, Bo Ram;Kim, Sang Jick;Yagita, Hideo;Croft, Michael;Kang, Young Jun
Toll样受体（TLR）信号传导的激活快速诱导炎性基因的表达，其持续确定的时间段。然而，不受控制和过度的炎症可能导致疾病的发展。4-1BB配体（4-1BBL）在巨噬细胞活化过程中通过与TLR相互作用维持炎性细胞因子的表达中起重要作用。在这里，我们表明，抑制4-1BBL信号减少巨噬细胞的炎症反应，并改善内毒素诱导的败血症小鼠。4-1BB-Fc融合蛋白通过阻断TLR 4和4-1BBL的寡聚化而显著降低巨噬细胞中的TNF产生。4-1BB-Fc的给药通过减少TNF的产生来抑制LPS诱导的脓毒症，并且抗TNF和4-1BB-Fc的共同给药提供了针对LPS诱导的脓毒症的更多保护。因此，这些观察结果表明，TLR/4-1BBL复合物形成的抑制可能在保护免受持续炎症方面非常有效，并且4-1BB-Fc治疗可能是炎性疾病的潜在治疗选择。
Activation of Toll-like receptor (TLR) signaling rapidly induces the expression of inflammatory genes, which is sustained for a defined period of time. However, uncontrolled and excessive inflammation may lead to the development of diseases. 4-1BB ligand (4-1BBL) plays an essential role in sustaining the expression of inflammatory cytokines by interacting with TLRs during macrophage activation. Here, we show that inhibition of 4-1BBL signaling reduced the inflammatory responses in macrophages and ameliorated endotoxin-induced sepsis in mice. A 4-1BB-Fc fusion protein significantly reduced TNF production in macrophages by blocking the oligomerization of TLR4 and 4-1BBL. Administration of 4-1BB-Fc suppressed LPS-induced sepsis by reducing TNF production, and the co-administration of anti-TNF and 4-1BB-Fc provided more protection against LPS-induced sepsis. Therefore, these observations suggest that inhibition of the TLR/4-1BBL complex formation may be highly efficacious in protecting against sustained inflammation, and that 4-1BB-Fc treatment may be a potential therapeutic option for inflammatory diseases.
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