Regulation of Toll-like receptor in airway infection

描述（由申请人提供）：不可分型的流感嗜血杆菌（NTHi）导致慢性阻塞性肺疾病（COPD）和中耳炎（OM）感染。两者都以炎症为特征。nthi诱导炎症的分子机制仍不明确。我们的长期目标是了解NTHi感染中炎症反应被诱导和调节的分子机制。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- κ b （nf - κ b）。由于TLR2在气道上皮细胞中的表达较低，而TLR2的过表达大大增强了NTHi诱导的NF-kappaB激活，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NF-kappaB和tgf - β阳性途径和EGFR-p38 MAPK阴性途径强烈上调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诱导的TLR2上调的分子机制奠定了坚实的基础（短期目标）。目的1。通过干扰NF-kappaB和tgf - β通路的信号传导，确定其对nthi诱导的TLR2上调的贡献。目标2。通过干扰其信号传导，确定EGFR-p38 MAPK通路对nthi诱导的TLR2上调的贡献。目标3。通过研究MKP-1表达增加对nthi诱导的p38激活和TLR2上调的影响，确定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诱导的TLR2上调的信号机制，不仅可以为炎症调节提供新的见解，还可以为调节COPD和OM的炎症反应开辟新的治疗靶点。此外，阐明糖皮质激素增强nthi诱导的TLR2上调的分子机制将为如何在临床中更恰当地使用糖皮质激素提供指导性信息。

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.