title: Novel cytoplasmic proteins of nontypeable Haemophilus influenzae up-regulate human MUC5AC mucin transcription via a positive p38 mitogen-activated protein kinase pathway and a negative phosphoinositide 3-kinase-Akt pathway.
abstract: Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen that causes chronic otitis media with effusion (COME) in children and exacerbation of chronic obstructive pulmonary disease (COPD) in adults. Mucin overproduction, a hallmark of both diseases, has been shown to directly cause conductive hearing loss in COME and airway obstruction in COPD. The molecular mechanisms underlying mucin overproduction in NTHi infections still remain unclear. Here, we show that NTHi strongly up-regulates MUC5AC mucin transcription only after bacterial cell disruption. Maximal up-regulation is induced by heat-stable bacterial cytoplasmic proteins, whereas NTHi surface membrane proteins induce only moderate MUC5AC transcription. These results demonstrate an important role for cytoplasmic molecules from lysed bacteria in the pathogenesis of NTHi infections, and may well explain why many patients still have persistent symptoms such as middle ear effusion in COME after intensive antibiotic treatment. Furthermore, our results indicate that activation of p38 mitogen-activated protein kinase is required for NTHi-induced MUC5AC transcription, whereas activation of phosphoinositide 3-kinase-Akt pathway leads to down-regulation of NTHi-induced MUC5AC transcription via a negative cross-talk with p38 mitogen-activated protein kinase pathway. These studies may bring new insights into molecular pathogenesis of NTHi infections and lead to novel therapeutic intervention for COME and COPD.
authors.affiliation: Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057, USA.
authors.forename: Beinan
authors.initials: B
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
authors.forename: Carol B
authors.initials: CB
authors.lastname: Basbaum
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D002458:Cell Fractionation; D002460:Cell Line; D002648:Child; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006192:Haemophilus Infections / Q000382:microbiology / Q000503:physiopathology; D006193:Haemophilus influenzae / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics* / Q000378:metabolism; D010034:Otitis Media with Effusion / Q000382:microbiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D029424:Pulmonary Disease, Chronic Obstructive / Q000382:microbiology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism*; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D055271:Mucin 5AC; D009077:Mucins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014764:Viral Proteins; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C524678:MUC5AC protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human