Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS
Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS
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DOI：
10.1073/pnas.0504226102
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发表时间：
2005-11-01
影响因子：
11.1
通讯作者：
Yui, K
中科院分区：
文献类型：
--
作者：
Honma, K;Udono, H;Yui, K
作为IFN调节因子（IRF）转录因子家族的成员，IRF-4在淋巴细胞和巨噬细胞/树突状细胞中表达。对IRF-4缺陷小鼠的研究揭示了IRF-4在淋巴细胞反应中的关键作用。然而，IRF-4在先天免疫应答中的作用尚不清楚。在这里，我们证明了IRF-4负调控巨噬细胞对toll样受体（TLR）刺激的促炎细胞因子的产生。缺乏IRF-4的小鼠对lps诱导的休克敏感，其巨噬细胞产生高水平的促炎细胞因子，包括tnf - α和IL-6，以响应TLR配体。通过小干扰RNA技术下调正常巨噬细胞中IRF-4的表达，以及巨噬细胞RAW264.7中IRF-4的过表达，证实了IRF-4对TLR刺激的抑制作用。IRF-4（-/-）巨噬细胞在lip刺激后，细胞因子产生的重要信号通路nf - κ B和JNK （c-Jun n -末端激酶）的激活增强。这些结果表明，IRF-4负调控TLR信号，并在TLR刺激下抑制促炎细胞因子的产生。
A member of the IFN regulatory factor (IRF) family of transcription factors, IRF-4 is expressed in lymphocytes and macrophage/dendritic cells. Studies using IRF-4-deficient mice have revealed the critical roles of IRF-4 in lymphocyte responses. However, the role of IRF-4 in innate immune responses is not clearly understood. Here, we demonstrate that IRF-4 negatively regulates the production of proinflammatory cytokines by macrophages in response to Toll-like receptor (TLR) stimulation. Mice lacking IRF-4 are sensitive to LPS-induced shock, and their macrophages produce high levels of proinflammatory cytokines, including TNF-alpha and IL-6, in response to TLR ligands. The inhibitory role of IRF-4 in response to TLR stimulation was confirmed by the down-regulation of IRF-4 expression in normal macrophages by using the small interfering RNA technique and by the overexpression of IRF-4 in macrophage line RAW264.7. Activation of the important signaling pathways for cytokine production, NF-kappa B and JNK (c-Jun N-terminal kinase), was enhanced after LIPS stimulation in IRF-4(-/-) macrophages. These results imply that IRF-4 negatively regulates TLR signaling and is inhibitory to the production of proinflammatory cytokines in response to TLR stimulation.