Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase
Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase
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DOI：
10.1074/jbc.m112190200
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发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Li, JD
中科院分区：
文献类型：
--
作者：
Shuto, T;Imasato, A;Li, JD
识别入侵微生物并诱导有效的先天免疫反应是宿主生存的关键。人类表面上皮细胞位于宿主-环境边界，因此是宿主抵御入侵微生物的第一道防线。它们通过表达在上皮细胞表面的Toll样受体(TLRs)识别微生物配体。TLR2已成为多种微生物配体的主要受体。与其在淋巴组织中的高表达不同，TLR2在上皮细胞中的表达水平较低。因此，目前尚不清楚TLR2在上皮细胞中的低表达是否足以介导细菌诱导的宿主防御和免疫反应，以及细菌在感染过程中是否会上调TLR2的表达。在这里，我们发现，尽管TLR2在未经刺激的人上皮细胞中表达水平非常低，但非分型流感嗜血杆菌(NTHi)极大地上调了TLR2的表达，NTHi是一种导致中耳炎和慢性阻塞性肺疾病的重要人类细菌病原体。TLR2的诱导需要激活依赖IKKbeta-IkappaBalpha的NF-kappaB通路，而抑制MKK3/6-p38α/β通路则可增强NTHi诱导的TLR2上调。令人惊讶的是，糖皮质激素，众所周知的有效抗炎药，协同增强ntri诱导的TLR2上调，可能是通过与p38 MAP激酶途径的负面串扰。这些研究可能为细菌和糖皮质激素在调节宿主防御和免疫反应中的作用带来新的见解，并导致调节中耳炎和慢性阻塞性肺疾病的天然免疫和炎症反应的新的治疗策略。
The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. TLR2 has gained importance as a major receptor for a variety of microbial ligands. In contrast to its high expression in lymphoid tissues, TLR2 is expressed at low level in epithelial cells. Thus, it remains unclear whether the low amount of TLR2 expressed in epithelial cells is sufficient for mediating bacteria-induced host defense and immune response and whether TLR2 expression can be upregulated by bacteria during infection. Here, we show that TLR2, although expressed at very low level in unstimulated human epithelial cells, is greatly up-regulated by nontypeable Hemophilus influenzae (NTHi), an important human bacterial pathogen causing otitis media and chronic obstructive pulmonary diseases. Activation of an IKKbeta-IkappaBalpha-dependent NF-kappaB pathway is required for TLR2 induction, whereas inhibition of the MKK3/6-p38alpha/beta pathway leads to enhancement of NTHi-induced TLR2 up-regulation. Surprisingly, glucocorticoids, well known potent anti-inflammatory agents, synergistically enhance NTRi-induced TLR2 up-regulation likely via a negative cross-talk with the p38 MAP kinase pathway. These studies may bring new insights into the role of bacteria and glucocorticoids in regulating host defense and immune response and lead to novel therapeutic strategies for modulating innate immune and inflammatory responses for otitis media and chronic obstructive pulmonary diseases.