BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages.
BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages.
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发表时间：
2004
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通讯作者：
Jennifer Wessells;M. Baer;H. Young;E. Claudio;K. Brown;U. Siebenlist;P. Johnson
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作者：
Jennifer Wessells;M. Baer;H. Young;E. Claudio;K. Brown;U. Siebenlist;P. Johnson
脂多糖（LPS）诱导巨噬细胞中肿瘤坏死因子α（TNF α）和其他促炎细胞因子的表达。在其诱导后，TNF α基因转录迅速减弱，部分原因是与TNF α启动子中的三个kappaB位点结合的NF-κ B p50同源二聚体的积累。在这里，我们研究了BCL-3的抑制作用，BCL-3是一种IkappaB样蛋白，专门与p50和p52同源二聚体相互作用。BCL-3由LPS诱导，具有延迟动力学，并且与核中的p50相关。BCL-3的强制表达抑制了LPS诱导的TNF α启动子的转录，并抑制了由优先结合p50二聚体的TNF α κ B位点组成的两个人工启动子。BCL-3介导的抑制被逆转，并通过HDAC-1的过表达增强，表明转录衰减涉及组蛋白脱乙酰酶的招募。对p50和BCL-3基因敲除小鼠巨噬细胞的分析显示，两种转录因子均负调控TNF α表达，BCL-3抑制IL-1 α和IL-1 β。相反，在BCL-3无效巨噬细胞中，抗炎细胞因子IL-10的诱导减少。BCL-3是不需要的生产p50同源二聚体，但BCL-3的表达在p50缺陷的细胞严重减少。总之，这些发现表明p50和BCL-3通过减弱促炎细胞因子的转录和激活IL-10表达在巨噬细胞中起抗炎调节剂的作用。
Lipopolysaccharide (LPS) induces expression of tumor necrosis factor alpha (TNFalpha) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFalpha gene transcription is rapidly attenuated, in part due to the accumulation of NF-kappaB p50 homodimers that bind to three kappaB sites in the TNFalpha promoter. Here we have investigated the inhibitory role of BCL-3, an IkappaB-like protein that interacts exclusively with p50 and p52 homodimers. BCL-3 was induced by LPS with delayed kinetics and was associated with p50 in the nucleus. Forced expression of BCL-3 suppressed LPS-induced transcription from the TNFalpha promoter and inhibited two artificial promoters composed of TNFalphakappaB sites that preferentially bind p50 dimers. BCL-3-mediated repression was reversed by trichostatin A and was enhanced by overexpression of HDAC-1, indicating that transcriptional attenuation involves recruitment of histone deacetylase. Analysis of macrophages from p50 and BCL-3 knock-out mice revealed that both transcription factors negatively regulate TNFalpha expression and that BCL-3 inhibits IL-1alpha and IL-1beta. In contrast, induction of the anti-inflammatory cytokine IL-10 was reduced in BCL-3 null macrophages. BCL-3 was not required for the production of p50 homodimers but BCL-3 expression was severely diminished in p50-deficient cells. Together, these findings indicate that p50 and BCL-3 function as anti-inflammatory regulators in macrophages by attenuating transcription of pro-inflammatory cytokines and activating IL-10 expression.