Regulation of Toll-like receptor in airway infection

Toll样受体在气道感染中的调节

• 批准号: 6730624
• 负责人: Jian-Dong Li
• 金额: $ 28.35万
• 依托单位: HOUSE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730624
• 关键词: Haemophilus influenzae; bacteria infection mechanism; biological signal transduction; cell line; enzyme induction /repression; gel mobility shift assay; glucocorticoids; immunoprecipitation; inflammation; mitogen activated protein kinase; neutralizing antibody; nuclear factor kappa beta; receptor expression; respiratory epithelium; respiratory infections; tissue /cell culture; toll like receptor; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): Non-typeable Haemophilus influenzae (NTHi) causes infections in chronic obstructive pulmonary disease (COPD) and otitis media (OM). Both are characterized by inflammation. The molecular mechanisms underlying NTHi-induced inflammation remain poorly defined. Our long-term objective is to understand the molecular mechanisms by which the inflammatory response is induced and regulated in NTHi infections. Our recent studies showed that NTHi strongly activates nuclear factor-kappaB (NF-kappaB) via Toll-like Receptor 2 (TLR2). Because TLR2 expression in airway epithelial cells is low and overexpression of TLR2 greatly enhances NTHi-induced NF-kappaB activation, we hypothesize that NTHi up-regulates TLR2 via a specific signaling network. Our preliminary results indeed indicate that NTHi strongly up-regulates TLR2 via positive NF-kappaB and TGF-beta pathways and a negative EGFR-p38 MAPK pathway. Moreover, glucocorticoids synergistically enhance NTHi-induced TLR2 up-regulation. These encouraging results have thus laid a solid foundation for further investigation of the molecular mechanisms underlying NTHi-induced TLR2 upregulation (short-term objective). Aim 1. Determine the contribution of NF-kappaB and TGF-beta pathways to NTHi-induced TLR2 up-regulation by perturbing their signaling. Aim 2. Determine the contribution of EGFR-p38 MAPK pathway to NTHi-induced TLR2 up-regulation by perturbing their signaling. Aim 3. Determine the signaling mechanisms by which glucocorticoids synergistically enhance NTHi-induced TLR2 up-regulation by studying the effect of increased MKP-1 expression on NTHi-induced activation of p38 and TLR2 up-regulation. Significance: Understanding the signaling mechanisms underlying NTHi-induced TLR2 up-regulation will not only bring new insights into the regulation of inflammation, but will also open up novel therapeutic targets for modulating inflammatory responses in COPD and OM. Moreover, elucidating the molecular mechanisms by which glucocorticoids enhance NTHi-induced TLR2 up-regulation will provide instructive information regarding how to use glucocorticoids more appropriately in the clinic.

描述（由申请人提供）：不可用的流感嗜血杆菌（NTHI）引起慢性阻塞性肺疾病（COPD）和耳炎培养基（OM）的感染。 两者都有炎症的特征。 NI-THI诱导的炎症的分子机制的定义仍然很差。 我们的长期目标是了解在NTHI感染中诱导并调节炎症反应的分子机制。 我们最近的研究表明，NTHI通过Toll样受体2（TLR2）强烈激活核因子-Kappab（NF-kappab）。 由于气道上皮细胞中的TLR2表达较低，TLR2的过表达极大地增强了NTHI诱导的NF-kappab激活，因此我们假设NTHI通过特定的信号网络上调TLR2。 我们的初步结果确实表明，NTHI通过阳性NF-kappab和TGF-beta途径和负EGFR-P38 MAPK途径强烈上调TLR2。 此外，糖皮质激素协同增强了NTHI诱导的TLR2上调。因此，这些令人鼓舞的结果为进一步研究NTHI诱导的TLR2上调（短期目标）的分子机制提供了坚实的基础。 AIM 1。通过扰动其信号传导来确定NF-kappab和TGF-beta途径对NTHI诱导的TLR2上调的贡献。 AIM 2。通过扰动其信号传导来确定EGFR-P38 MAPK途径对NTHI诱导的TLR2上调的贡献。 AIM 3。确定糖皮质激素通过研究增加MKP-1表达对NTHI诱导的p38和TLR2上调激活的影响来协同增强NTHI诱导的TLR2上调的信号传导机制。 意义：了解NTHI诱导的TLR2上调的信号传导机制不仅会为炎症的调节带来新的见解，而且还将为调节COPD和OM中炎症反应的新型治疗靶标提供。 此外，阐明糖皮质激素增强NTHI诱导的TLR2上调的分子机制将提供有关如何在诊所中更适当使用糖皮质激素的启发性信息。