MEK Is a Key Modulator for TLR5-induced Interleukin-8 and MIP3α Gene Expression in Non-transformed Human Colonic Epithelial Cells*
MEK Is a Key Modulator for TLR5-induced Interleukin-8 and MIP3α Gene Expression in Non-transformed Human Colonic Epithelial Cells*
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MEK 是非转化人结肠上皮细胞中 TLR5 诱导的 IL-8 和 MIP3α 基因表达的关键调节剂*
DOI：
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发表时间：
2004
影响因子：
4.8
通讯作者：
C. Pothoulakis
中科院分区：
文献类型：
--
作者：
S. Rhee;A. C. Keates;M. Moyer;C. Pothoulakis
鞭毛蛋白是Toll样受体5(TLR5)的特异性配体，是一种与多种细菌相关的分子模式。近年来，人们对TLR信号进行了深入的研究。然而，未转化的结肠细胞中的TLR5相关信号尚未被研究。在这里，我们研究了鞭毛蛋白诱导未转化的人结肠NCM460细胞中细胞因子的表达及其介导这些反应的信号机制。细胞因子表达阵列实验显示，鞭毛蛋白(100 ng/ml)作用于细胞12h后，IL-8和巨噬细胞炎性蛋白3α(MIP3α)的表达呈TLR5特异性增加。鞭毛蛋白还能激活MAP激酶(ERK1/2、Jnk和p38)并降解IκBα。显性负性MEK1(一种激活ERK1/2的激酶)可阻断鞭毛蛋白刺激的IL-8和MIP3α转录活性，而MEK特异性抑制剂PD98059和U0126则减少这些细胞因子的蛋白质产生。相反，转染组活性MEK1可增加IL-8和MIP3α转录活性，且不依赖于NFκB。此外，过表达固有活性的MEK1可诱导IL-8和MIP3α蛋白的产生。我们还证明TRAF6的C末端卷曲和TRAF-C结构域不能介导NFκB的激活，但参与了MEK介导的IL-8和MIP3α的表达。因此，在未转化的人结肠细胞中，鞭毛蛋白/TLR5结合后的MEK激活是NF-κB非依赖性、IL-8和MIP3α表达的关键调节因子。
Flagellin, a specific ligand for Toll-like receptor 5 (TLR5), is a molecular pattern associated with several bacterial species. Recently, TLR signaling has been intensively studied. However, TLR5-associated signaling in non-transformed colonocytes has not been investigated. Here we studied the expression of cytokines induced by flagellin in non-transformed human colonic NCM460 cells and the signaling mechanisms mediating these responses. Cytokine expression array experiments showed that exposure of the cells to flagellin (100 ng/ml) for 12 h increased the expression of interleukin (IL)-8 and macrophage-inflammatory protein 3α (MIP3α) in a TLR5-specific manner. Flagellin also activated MAP kinases (ERK1/2, JNK, and p38) and degraded IκBα. Dominant negative MEK1 (a kinase that activates ERK1/2) blocked flagellin-stimulated IL-8 and MIP3α transcriptional activity, while the MEK-specific inhibitors PD98059 and U0126 reduced protein production of these cytokines. Conversely, transfection with a constitutively active MEK1 increased IL-8 and MIP3α transcriptional activity in a NFκB-independent manner. Furthermore, overexpression of the constitutively active MEK1 induced IL-8 and MIP3α protein production. We also demonstrated that C-terminal coiled-coil and TRAF-C domains of TRAF6, unable to mediate NFκB activation, are involved in MEK-mediated IL-8 and MIP3α expression. Thus, in non-transformed human colonocytes, MEK activation following flagellin/TLR5 engagement is a key modulator for NFκB-independent, IL-8 and MIP3α expression.
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影响因子：
3.7
作者：
Natarajan, R;Gupta, S;Fowler, AA
通讯作者：
Fowler, AA
影响因子：
20.3
作者：
Guha, M;O'Connell, MA;Mackman, N
通讯作者：
Mackman, N
NF-kappa B 是肠道侵袭性细菌感染诱导的肠上皮细胞先天免疫反应的中心调节因子。
DOI：
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发表时间：
1999
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Elewaut,D;DiDonato,JA;Kim,JM;Truong,F;Eckmann,L;Kagnoff,MF
通讯作者：
Kagnoff,MF
影响因子：
4.3
作者：
Giese S;Hossain H;Markmann M;Chakraborty T;Tchatalbachev S;Guillou F;Bergmann M;Failing K;Weider K;Brehm R
通讯作者：
Brehm R
影响因子：
56.9
作者：
Hooper, LV;Wong, MH;Gordon, JI
通讯作者：
Gordon, JI