Regulation of Toll-like receptor in airway infection

描述(申请人提供)：非分型流感嗜血杆菌(NTHi)可引起慢性阻塞性肺疾病(COPD)和中耳炎(OM)的感染。两者都以炎症为特征。NTHi诱导炎症的分子机制仍不清楚。我们的长期目标是了解在NTHi感染中诱导和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TLR2在呼吸道上皮细胞中低表达，过表达TLR2可显著增强NTHi诱导的NF-kappaB活性，我们推测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通过阳性的NF-kappaB和转化生长因子-β途径以及阴性的EGFR-p38MAPK途径强烈上调TLR2。此外，糖皮质激素可协同增强NTHi诱导的TLR2上调。这些令人鼓舞的结果为进一步研究NTHi诱导TLR2上调的分子机制(短期目标)奠定了坚实的基础。目的1.通过干扰核因子-kappaB和转化生长因子-β信号通路在NTHi诱导的TLR2上调中的作用。目的2.通过干扰EGFR-p38MAPK信号通路，确定EGFR-p38MAPK通路在NTHi诱导TLR2上调中的作用。目的3.通过研究MKP-1表达增加对NTHi诱导的p38和TLR2上调的影响，探讨糖皮质激素协同增强NTHi诱导的TLR2上调的信号机制。意义：了解NTHi诱导TLR2上调的信号机制不仅将为炎症的调控带来新的见解，而且将为调节COPD和OM的炎症反应开辟新的治疗靶点。此外，阐明糖皮质激素促进NTHi诱导的TLR2上调的分子机制将为如何在临床上更恰当地使用糖皮质激素提供有益的信息。

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.