title: Phosphodiesterase 4B mediates extracellular signal-regulated kinase-dependent up-regulation of mucin MUC5AC protein by Streptococcus pneumoniae by inhibiting cAMP-protein kinase A-dependent MKP-1 phosphatase pathway.
abstract: Otitis media (OM) is the most common childhood bacterial infection and the major cause of conductive hearing loss in children. Mucus overproduction is a hallmark of OM. Streptococcus pneumoniae is the most common gram-positive bacterial pathogen causing OM. Among many mucin genes, MUC5AC has been found to be greatly up-regulated in the middle ear mucosa of human patients with OM. We previously reported that S. pneumoniae up-regulates MUC5AC expression in a MAPK ERK-dependent manner. We also found that MAPK phosphatase-1 (MKP-1) negatively regulates S. pneumoniae-induced ERK-dependent MUC5AC up-regulation. Therapeutic strategies for up-regulating the expression of negative regulators such as MKP-1 may have significant therapeutic potential for treating mucus overproduction in OM. However, the underlying molecular mechanism by which MKP-1 expression is negatively regulated during S. pneumoniae infection is unknown. In this study we show that phosphodiesterase 4B (PDE4B) mediates S. pneumoniae-induced MUC5AC up-regulation by inhibiting the expression of a negative regulator MKP-1, which in turn leads to enhanced MAPK ERK activation and subsequent up-regulation of MUC5AC. PDE4B inhibits MKP-1 expression in a cAMP-PKA-dependent manner. PDE4-specific inhibitor rolipram inhibits S. pneumoniae-induced MUC5AC up-regulation both in vitro and in vivo. Moreover, we show that PDE4B plays a critical role in MUC5AC induction. Finally, topical and post-infection administration of rolipram into the middle ear potently inhibited S. pneumoniae-induced MUC5AC up-regulation. Collectively, these data demonstrate that PDE4B mediates ERK-dependent up-regulation of mucin MUC5AC by S. pneumoniae by inhibiting cAMP-PKA-dependent MKP-1 pathway. This study may lead to novel therapeutic strategy for inhibiting mucus overproduction.
authors.affiliation: Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lee
authors.forename: Kensei
authors.initials: K
authors.lastname: Komatsu
authors.forename: Byung Cheol
authors.initials: BC
authors.lastname: Lee
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.forename: Z John
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004432:Ear, Middle / Q000166:cytology / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000382:microbiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000378:metabolism*; D009093:Mucus / Q000378:metabolism; D010033:Otitis Media / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011008:Pneumococcal Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D034741:RNA, Small Interfering; D017868:Cyclic AMP-Dependent Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C543000:PDE4B protein, mouse