title: Activation of epidermal growth factor receptor is required for NTHi-induced NF-κB-dependent inflammation.
abstract: BACKGROUND
  Inflammation is a hallmark of many serious human diseases. Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing respiratory tract infections in both adults and children. NTHi infections are characterized by inflammation, which is mainly mediated by nuclear transcription factor-kappa B (NF-κB)-dependent production of proinflammatory mediators. Epidermal growth factor receptor (EGFR) has been shown to play important roles in regulating diverse biological processes, including cell growth, differentiation, apoptosis, adhesion, and migration. Its role in regulating NF-κB activation and inflammation, however, remains largely unknown.
  
  
  RESULTS
  In the present study, we demonstrate that EGFR plays a vital role in NTHi-induced NF-κB activation and the subsequent induction of proinflammatory mediators in human middle ear epithelial cells and other cell types. Importantly, we found that AG1478, a specific tyrosine kinase inhibitor of EGFR potently inhibited NTHi-induced inflammatory responses in the middle ears and lungs of mice in vivo. Moreover, we found that MKK3/6-p38 and PI3K/Akt signaling pathways are required for mediating EGFR-dependent NF-κB activation and inflammatory responses by NTHi.
  
  
  CONCLUSIONS
  Here, we provide direct evidence that EGFR plays a critical role in mediating NTHi-induced NF-κB activation and inflammation in vitro and in vivo. Given that EGFR inhibitors have been approved in clinical use for the treatment of cancers, current studies will not only provide novel insights into the molecular mechanisms underlying the regulation of inflammation, but may also lead to the development of novel therapeutic strategies for the treatment of respiratory inflammatory diseases and other inflammatory diseases.
authors: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America. Xiangbin_Xu@urmc.rochester.edu
authors: Xiangbin
authors: X
authors: Xu
authors: Rachel R
authors: RR
authors: Steere
authors: Christine A
authors: CA
authors: Fedorchuk
authors: Jinjiang
authors: J
authors: Pang
authors: Ji-Yun
authors: JY
authors: Lee
authors: Jae Hyang
authors: JH
authors: Lim
authors: Haidong
authors: H
authors: Xu
authors: Zhixing K
authors: ZK
authors: Pan
authors: Sanjay B
authors: SB
authors: Maggirwar
authors: Jian-Dong
authors: JD
authors: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D004432:Ear, Middle / Q000473:pathology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000382:microbiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006193:Haemophilus influenzae / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000382:microbiology* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D066246:ErbB Receptors; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt