CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression
CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression
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DOI：
10.4049/jimmunol.166.1.574
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发表时间：
2001-01-01
影响因子：
4.4
通讯作者：
Vogel, SN
中科院分区：
文献类型：
--
作者：
Perera, PY;Mayadas, TN;Vogel, SN
巨噬细胞对革兰氏阴性脂多糖的过度产生炎症介质与感染性休克有关。最近的报道表明，三种膜相关蛋白，CD 14、CD 11b/CD 18和Toll样受体（TLR）4，可能在小鼠巨噬细胞中充当LPS识别和/或信号传导受体。因此，这些蛋白在诱导环加氧酶2（考克斯-2）、IL-12 p35、IL-12 p40、TNF-α、IFN-诱导蛋白（IP）-10、和IFN共有序列结合蛋白（ICSBP）基因对LPS或LPS模拟物紫杉醇的反应，使用来自这些膜相关蛋白缺陷小鼠的巨噬细胞进行检查。所选择的基因组反映了有助于脓毒性休克发病机制的多种巨噬细胞效应子功能。响应于低浓度的LPS或紫杉醇的整个基因组的诱导需要CD 14和TLR 4两者的参与，而高浓度的LPS或紫杉醇在不存在CD 14的情况下引发LPS诱导基因的子集的表达。相反，对于考克斯-2、IL-12 p35、IL-12 p35和IL-12 p35的最佳诱导，IL-12 p40基因表达水平与低浓度LPS或所有浓度Taxol的表达水平呈负相关，还需要CD 11b/CD 18。CD 11b/CD 11缺陷型巨噬细胞对考克斯-2、IL-12 p35和IL-12 p40基因表达的诱导减弱与对紫杉醇应答的NF-κ B核转位和丝裂原活化蛋白激酶（MAPK）活化以及对LPS应答的NF-κ B核转位的显著抑制相关。CD 14、TLR 4和CD 11b/CD 18必须协调参与，以向巨噬细胞传递最佳信号。
Overproduction of inflammatory mediators by macrophages in response to Gram-negative LPS has been implicated in septic shock. Recent reports indicate that three membrane-associated proteins, CD14, CD11b/CD18, and Toll-like receptor (TLR) 4, may serve as LPS recognition and/or signaling receptors in murine macrophages, Therefore, the relative contribution of these proteins in the induction of cyclooxygenase 2 (COX-2), IL-12 p35, IL-12 p40, TNF-alpha, IFN-inducible protein (IP)-10, and IFN consensus sequence binding protein (ICSBP) genes in response to LPS or the LPS-mimetic, Taxol, was examined using macrophages derived from mice deficient for these membrane-associated proteins. The panel of genes selected reflects diverse macrophage effector functions that contribute to the pathogenesis of septic shock. Induction of the entire panel of genes in response to low concentrations of LPS or Taxol requires the participation of both CD14 and TLR4, whereas high concentrations of LPS or Taxol elicit the expression of a subset of LPS-inducible genes in the absence of CD14, In contrast, for optimal induction of COX-2, IL-12 p35, and IL-12 p40 genes by low concentrations of LPS or by all concentrations of Taxol, CD11b/CD18 was also required. Mitigated induction of COX-2, IL-12 p35, and IL-12 p40 gene expression by CD11b/CD11-deficient macrophages correlated with a marked inhibition of NF-kappaB nuclear translocation and mitogen-activated protein kinase (MAPK) activation in response to Taxol and of NF-kappaB nuclear translocation in response to LPS, These findings suggest that for expression of a full repertoire of LPS-/Taxol-inducible genes, CD14, TLR4, and CD11b/CD18 must be coordinately engaged to deliver optimal signaling to the macrophage.