Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL070293-01A1
Application #
6574004
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Croxton, Thomas
Project Start
2003-04-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$333,500
Indirect Cost

  Institution

Name
House Ear Institute
Department
Type
DUNS #
062076989
City
Los Angeles
State
CA
Country
United States
Zip Code
90057

  Publications

Kweon, Soo-Mi; Wang, Beinan; Rixter, Davida et al. (2006) Synergistic activation of NF-kappaB by nontypeable H. influenzae and S. pneumoniae is mediated by CK2, IKKbeta-IkappaBalpha, and p38 MAPK. Biochem Biophys Res Commun 351:368-75
Mikami, Fumi; Lim, Jae Hyang; Ishinaga, Hajime et al. (2006) The transforming growth factor-beta-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacteria via a dual mechanism involving functional cooperation with NF-kappaB and MAPK phosphatase 1-dependent negative cross-talk with p38 MA J Biol Chem 281:22397-408
Mikami, Fumi; Gu, He; Jono, Hirofumi et al. (2005) Epidermal growth factor receptor acts as a negative regulator for bacterium nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling pathway. J Biol Chem 280:36185-94
Yoshida, Hiroki; Jono, Hirofumi; Kai, Hirofumi et al. (2005) The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem 280:41111-21
Jono, Hirofumi; Lim, Jae Hyang; Chen, Lin-Feng et al. (2004) NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. J Biol Chem 279:36171-4
Sakai, Akihiro; Han, Jiahuai; Cato, Andrew C B et al. (2004) Glucocorticoids synergize with IL-1beta to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells. BMC Mol Biol 5:2
Chen, Ran; Lim, Jae Hyang; Jono, Hirofumi et al. (2004) Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochem Biophys Res Commun 324:1087-94
Watanabe, Takahiro; Jono, Hirofumi; Han, Jiahuai et al. (2004) Synergistic activation of NF-kappaB by nontypeable Haemophilus influenzae and tumor necrosis factor alpha. Proc Natl Acad Sci U S A 101:3563-8