Regulation of Toll-like receptor in airway infection

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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.