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Mary C Rose - One of the best experts on this subject based on the ideXlab platform.

  • a novel dissociative steroid vbp15 reduces MUC5AC gene expression in airway epithelial cells but lacks the gre mediated transcriptional properties of dexamethasone
    Pulmonary Pharmacology & Therapeutics, 2016
    Co-Authors: Lindsay M Garvin, Mary C Rose, Yajun Chen, Jesse M Damsker
    Abstract:

    Overproduction of secretory mucins contributes to morbidity/mortality in inflammatory lung diseases. Inflammatory mediators directly increase expression of mucin genes, but few drugs have been shown to directly repress mucin gene expression. IL-1β upregulates the MUC5AC mucin gene in part via the transcription factors NFκB while the glucocorticoid Dexamethasone (Dex) transcriptionally represses MUC5AC expression by Dex-activated GR binding to two GRE cis-sites in the MUC5AC promoter in lung epithelial cells. VBP compounds (ReveraGen BioPharma) maintain anti-inflammatory activity through inhibition of NFκB but exhibit reduced GRE-mediated transcriptional properties associated with adverse side-effects and thus have potential to minimize harmful side effects of long-term steroid therapy in inflammatory lung diseases. We investigated VBP15 efficacy as an anti-mucin agent in two types of airway epithelial cells and analyzed the transcription factor activity and promoter binding associated with VBP15-induced MUC5AC repression. VBP15 reduced MUC5AC mRNA abundance in a dose- and time-dependent manner similar to Dex in the presence or absence of IL-1β in A549 and differentiated human bronchial epithelial cells. Repression was abrogated in the presence of RU486, demonstrating a requirement for GR in the VBP15-induced repression of MUC5AC. Inhibition of NFκB activity resulted in reduced baseline expression of MUC5AC indicating that constitutive activity maintains MUC5AC production. Chromatin immunoprecipitation analysis demonstrated lack of GR and of p65 (NFκB) binding to composite GRE domains in the MUC5AC promoter following VBP15 exposure of cells, in contrast to Dex. These data demonstrate that VBP15 is a novel anti-mucin agent that mediates the reduction of MUC5AC gene expression differently than the classical glucocorticoid, Dex.

  • il 1β induction of MUC5AC gene expression is mediated by creb and nf κb and repressed by dexamethasone
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2014
    Co-Authors: Yajun Chen, Tracey J Nickola, Anamaris M Colbergpoley, Lindsay M Garvin, Alan Watson, Mary C Rose
    Abstract:

    Chronic airway diseases are characterized by inflammation and mucus overproduction. The MUC5AC mucin gene is upregulated by the proinflammatory cytokine interleukin-1 β (IL-1β) via activation of cAMP response element-binding protein (CREB) in the NCI-H292 cancer cell line and nuclear factor-κB (NF-κB) in the HBE1 transformed cell line, with each transcription factor binding to a cognate cis site in the proximal or distal region, respectively, of the MUC5AC promoter. We utilized primary differentiated human bronchial epithelial (HBE) and A549 lung adenocarcinoma cells to further investigate the contributions of CREB and NF-κB subunits to the IL-1β-induced upregulation of MUC5AC. Data show that ligand binding of IL-1β to the IL-1β receptor is required to increase MUC5AC mRNA abundance. Chromatin immunoprecipitation analyses show direct binding of CREB to the previously identified cAMP response element site and binding of p65 and p50 subunits to a novel NF-κB site in a mucin-regulatory domain in the proximal promoter and to a previously identified NF-κB site in the distal promoter. P50 binds to both NF-κB sites at 1 h following IL-1β exposure, but is replaced at 2 h by p65 in A549 cells and by a p50/p65 heterodimer in HBE cells. Thus IL-1β activates multiple domains in the MUC5AC promoter but exhibits some cell-specific responses, highlighting the complexity of MUC5AC transcriptional regulation. Data show that dexamethasone, a glucocorticoid that transcriptionally represses MUC5AC gene expression under constitutive conditions, also represses IL-1β-mediated upregulation of MUC5AC gene expression. A further understanding of mechanisms mediating MUC5AC regulation should lead to a honing of therapeutic approaches for the treatment of mucus overproduction in inflammatory lung diseases.

  • IL-8 Regulates Mucin Gene Expression at the Posttranscriptional Level in Lung Epithelial Cells
    Journal of Immunology, 2009
    Co-Authors: Maria V. Bautista, Vessela S. Ivanova, Michael Rahimi, Alan M Watson, Yajun Chen, Mary C Rose
    Abstract:

    Airway inflammation and mucus hypersecretion/overproduction/obstruction are pathophysiological characteristics of cystic fibrosis, asthma, and chronic obstructive pulmonary disease. Up-regulation of airway mucin genes by inflammatory/immune response mediators is one of the major contributors to mucin overproduction. IL-8, a potent proinflammatory mediator and neutrophil chemoattractant, is present at high levels in the airway secretions of such patients. In this study, the effects of IL-8 on expression of two major airway mucin genes, MUC5AC and MUC5B , were evaluated. IL-8 increased the mRNA abundance of both mucin genes in two human respiratory tract-derived cell lines (A549 and NCI-H292) in a time- and concentration-dependent manner. IL-8 also increased MUC5AC and MUC5B mRNA levels in primary normal differentiated human bronchial epithelial cells, with a high concentration of IL-8 required to increase MUC5B mRNA levels. IL-8 did not transcriptionally up-regulate MUC5AC gene expression, but rather increased the stability of the MUC5AC transcript, suggesting regulation at the posttranscriptional level. In addition, IL-8 altered the levels of RNA-binding proteins to specific domains in the 3′-untranslated region of the MUC5AC transcript. Taken together, these data indicate that the IL-8-induced binding of RNA-binding proteins to the 3′-untranslated region of MUC5AC is a potential mechanism for regulating MUC5AC gene expression at the posttranscriptional level, thus suggesting a new role whereby IL-8 sustains mucin gene expression in inflamed airways.

  • dexamethasone mediated repression of MUC5AC gene expression in human lung epithelial cells
    American Journal of Respiratory Cell and Molecular Biology, 2006
    Co-Authors: Yajun Chen, Tracey J Nickola, Nancy L Difronzo, Anamaris M Colbergpoley, Mary C Rose
    Abstract:

    Glucocorticoids regulate gene expression via binding of the ligand-activated glucocorticoid receptor (GR) to glucocorticoid-responsive elements (GRE) in target gene promoters. The MUC5AC gene, which encodes the protein backbone of an abundant secreted airway mucin, has several putative GRE cis-elements in its 5' sequence. Mechanism(s) whereby glucocorticoids regulate mucin genes have not previously been described. In this study, the glucocorticoid dexamethasone (Dex) decreased MUC5AC mRNA abundance in A549 and NCI-H292 cell lines and primary differentiated normal bronchial epithelial cells by 50-80%, suggesting a common mechanism of MUC5AC gene repression in human lung epithelial cells. Kinetic analyses showed that MUC5AC mRNA was not significantly decreased until 6 h after Dex exposure, and that nuclear translocation of GR was biphasic, suggesting that Dex-mediated cis-repression of MUC5AC gene expression was a delayed response of GR translocation. Transfection analyses demonstrated that Dex transcriptionally repressed the MUC5AC promoter. Electrophoretic mobility shift assays with wild-type and mutant oligonucleotide probes showed that GR bound to two GRE cis-sites (nucleotides -930 to -912 and -369 to -351) in the MUC5AC promoter. Analyses of mutated MUC5AC promoter constructs demonstrated that NF-kappaB cis-sites were not involved in Dex-mediated repression of MUC5AC. Dex did not alter mRNA stability of MUC5AC transcripts. Taken together, the data indicate that Dex transcriptionally mediates repression of MUC5AC gene expression in human lung epithelial cells at quiescent states after binding of GR to one or more GRE cis-elements in the MUC5AC promoter.

  • Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells.
    American Journal of Physiology-Lung Cellular and Molecular Physiology, 1999
    Co-Authors: Judith A. Voynow, Mary C Rose, Lisa Rosenthal Young, Yiqiong Wang, Teresa Horger, Bernard M. Fischer
    Abstract:

    Chronic neutrophil-predominant inflammation and hypersecretion of mucus are common pathophysiological features of cystic fibrosis, chronic bronchitis, and viral- or pollution-triggered asthma. Neutrophils release elastase, a serine protease, that causes increased mucin production and secretion. The molecular mechanisms of elastase-induced mucin production are unknown. We hypothesized that as part of this mechanism, elastase upregulates expression of a major respiratory mucin gene, MUC5AC. A549, a human lung carcinoma cell line that expresses MUC5AC mRNA and protein, and normal human bronchial epithelial cells in an air-liquid interface culture were stimulated with neutrophil elastase. Neutrophil elastase increased MUC5AC mRNA levels in a time-dependent manner in both cell culture systems. Neutrophil elastase treatment also increased MUC5AC protein levels in A549 cells. The mechanism of MUC5AC gene regulation by elastase was determined in A549 cells. The induction of MUC5AC gene expression required serine protease activity; other classes of proteases had no effect on MUC5AC gene expression. Neutrophil elastase increased MUC5AC mRNA levels by enhancing mRNA stability. This is the first report of mucin gene regulation by this mechanism.

Robert Langenbach - One of the best experts on this subject based on the ideXlab platform.

  • MUC5AC null mice are predisposed to spontaneous gastric antro-pyloric hyperplasia and adenomas coupled with attenuated H. pylori-induced corpus mucous metaplasia
    Laboratory Investigation, 2019
    Co-Authors: Sureshkumar Muthupalani, Robert Langenbach, Joanna Joy, Yan Feng, Carrie Dobey, Hye-youn Cho, Timothy C. Wang, Susan J. Hagen, James G. Fox
    Abstract:

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide and is strongly associated with chronic Helicobacter pylori ( Hp ) infection. The ability of Hp to closely adhere to the gastric surface protective mucous layer containing mucins (MUC in humans and Muc in animals), primarily MUC5AC, is integral in the stepwise pathogenesis from gastritis to cancer. To probe the role of MUC5AC in Hp -induced gastric pathology, MUC5AC ^ −/− and MUC5AC ^ +/+ (WT) mice were experimentally infected with Hp Sydney strain (SS1). At 16 weeks and 32 weeks post infection (wpi), groups of mice were euthanized and evaluated for the following: gastric histopathological parameters, immunohistochemical expression of mucins (MUC5AC, Muc1, Muc2), Trefoil factor family proteins (Tff1 and Tff2), Griffonia ( Bandeiraea ) simplicifolia lectin II (GSL II) (mucous metaplasia marker) and Clusterin (Spasmolytic Polypeptide Expressing Metaplasia (SPEM) marker), Hp colonization density by qPCR and gastric cytokine mRNA levels. Our results demonstrate that MUC5AC ^ −/− mice developed spontaneous antro-pyloric proliferation, adenomas and in one case with neuroendocrine differentiation; these findings were independent of Hp infection along with strong expression levels of Tff1, Tff2 and Muc1. Hp -infected MUC5AC ^ −/− mice had significantly lowered gastric corpus mucous metaplasia at 16 wpi and 32 wpi ( P  = 0.0057 and P  = 0.0016, respectively), with a slight reduction in overall gastric corpus pathology. GSII-positive mucous neck cells were decreased in Hp -infected MUC5AC ^ −/− mice compared to WT mice and clusterin positivity was noted within metaplastic glands in both genotypes following Hp infection. Additionally, Hp colonization densities were significantly higher in MUC5AC ^ −/− mice compared to WT at 16 wpi in both sexes ( P  = 0.05) along with a significant reduction in gastric Tnfα (16 wpi—males and females, P  = 0.017 and P  = 0.036, respectively and 32 wpi—males only, P  = 0.025) and Il-17a (16 wpi—males) ( P  = 0.025). Taken together, our findings suggest a protective role for MUC5AC/MUC5AC in maintaining gastric antral equilibrium and inhibiting Hp colonization and associated inflammatory pathology. The authors show that MUC5AC ^ −/− mice develop spontaneous gastric antro-pyloric hyperplasia and adenomas. Interestingly, MUC5AC ^ −/− mice have suppression of gastric corpus mucous metaplasia and key proinflammatory cytokines ( Tnfα and Il-17a) in a setting of enhanced Helicobacter pylori colonization, thus implying a complex role for MUC5AC in gastric homeostasis.

  • interleukin 1β induced mucin production in human airway epithelium is mediated by cyclooxygenase 2 prostaglandin e2 receptors and cyclic amp protein kinase a signaling
    Molecular Pharmacology, 2004
    Co-Authors: Thomas Gray, Paul Nettesheim, Charles D Loftin, James C Bonner, Shyamal D Peddada, Robert Langenbach
    Abstract:

    We reported recently that interleukin (IL)-1β exposure resulted in a prolonged increase in MUC5AC mucin production in normal, well differentiated, human tracheobronchial epithelial (NHTBE) cell cultures, without significantly increasing MUC5AC mRNA ( Am J Physiol 286: L320–L330, 2004). The goal of the present study was to elucidate the signaling pathways involved in IL-1β–induced MUC5AC production. We found that IL-1β increased cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin (PG) E 2 production and that the COX-2 inhibitor celecoxib suppressed IL-1β–induced MUC5AC production. Addition of exogenous PGE 2 to NHTBE cultures also increased MUC5AC production and IL-1β–induced MUC5AC hypersecretion in tracheas from wild-type but not from COX-2–/– mice. NHTBE cells expressed all four E-prostanoid (EP) receptor subtypes and misoprostol, an EP2 and EP4 agonist, increased MUC5AC production, whereas sulprostone, an EP1 and EP3 agonist, did not. Furthermore, specific protein kinase A (PKA) inhibitors blocked IL-1β and PGE 2 -induced MUC5AC production. However, neither inhibition of epidermal growth factor receptor (EGFR) activation with the tyrosine kinase inhibitor 4-(3-chloroanilino)-6,7-dimethoxyquinazoline HCl (AG-1478) or EGFR blocking antibody nor inhibition of extracellular signal-regulated kinase/P-38 mitogen activated protein kinases with specific inhibitors blocked IL-1β stimulation of MUC5AC mucin production. We also observed that tumor necrosis factor (TNF)-α, platelet activating factor (PAF), and lipopolysaccharide (LPS) induced COX-2 and increased MUC5AC production that was blocked by celecoxib, suggesting a common signaling pathway of inflammatory mediator-induced MUC5AC production in NHTBE cells. We conclude that the induction of MUC5AC by IL-1β, TNF-α, PAF, and LPS involves COX-2– generated PGE 2 , activation of EP2 and/or EP4 receptor(s), and cAMP-PKA–mediated signaling.

James G. Fox - One of the best experts on this subject based on the ideXlab platform.

  • MUC5AC null mice are predisposed to spontaneous gastric antro-pyloric hyperplasia and adenomas coupled with attenuated H. pylori-induced corpus mucous metaplasia
    Laboratory Investigation, 2019
    Co-Authors: Sureshkumar Muthupalani, Robert Langenbach, Joanna Joy, Yan Feng, Carrie Dobey, Hye-youn Cho, Timothy C. Wang, Susan J. Hagen, James G. Fox
    Abstract:

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide and is strongly associated with chronic Helicobacter pylori ( Hp ) infection. The ability of Hp to closely adhere to the gastric surface protective mucous layer containing mucins (MUC in humans and Muc in animals), primarily MUC5AC, is integral in the stepwise pathogenesis from gastritis to cancer. To probe the role of MUC5AC in Hp -induced gastric pathology, MUC5AC ^ −/− and MUC5AC ^ +/+ (WT) mice were experimentally infected with Hp Sydney strain (SS1). At 16 weeks and 32 weeks post infection (wpi), groups of mice were euthanized and evaluated for the following: gastric histopathological parameters, immunohistochemical expression of mucins (MUC5AC, Muc1, Muc2), Trefoil factor family proteins (Tff1 and Tff2), Griffonia ( Bandeiraea ) simplicifolia lectin II (GSL II) (mucous metaplasia marker) and Clusterin (Spasmolytic Polypeptide Expressing Metaplasia (SPEM) marker), Hp colonization density by qPCR and gastric cytokine mRNA levels. Our results demonstrate that MUC5AC ^ −/− mice developed spontaneous antro-pyloric proliferation, adenomas and in one case with neuroendocrine differentiation; these findings were independent of Hp infection along with strong expression levels of Tff1, Tff2 and Muc1. Hp -infected MUC5AC ^ −/− mice had significantly lowered gastric corpus mucous metaplasia at 16 wpi and 32 wpi ( P  = 0.0057 and P  = 0.0016, respectively), with a slight reduction in overall gastric corpus pathology. GSII-positive mucous neck cells were decreased in Hp -infected MUC5AC ^ −/− mice compared to WT mice and clusterin positivity was noted within metaplastic glands in both genotypes following Hp infection. Additionally, Hp colonization densities were significantly higher in MUC5AC ^ −/− mice compared to WT at 16 wpi in both sexes ( P  = 0.05) along with a significant reduction in gastric Tnfα (16 wpi—males and females, P  = 0.017 and P  = 0.036, respectively and 32 wpi—males only, P  = 0.025) and Il-17a (16 wpi—males) ( P  = 0.025). Taken together, our findings suggest a protective role for MUC5AC/MUC5AC in maintaining gastric antral equilibrium and inhibiting Hp colonization and associated inflammatory pathology. The authors show that MUC5AC ^ −/− mice develop spontaneous gastric antro-pyloric hyperplasia and adenomas. Interestingly, MUC5AC ^ −/− mice have suppression of gastric corpus mucous metaplasia and key proinflammatory cytokines ( Tnfα and Il-17a) in a setting of enhanced Helicobacter pylori colonization, thus implying a complex role for MUC5AC in gastric homeostasis.

Il Yup Chung - One of the best experts on this subject based on the ideXlab platform.

  • s100a8 s100a9 and s100a12 activate airway epithelial cells to produce MUC5AC via extracellular signal regulated kinase and nuclear factor κb pathways
    Immunology, 2015
    Co-Authors: Jin Hyun Kang, Sae Mi Hwang, Il Yup Chung
    Abstract:

    Airway mucus hyperproduction is a common feature of chronic airway diseases such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis, which are closely associated with neutrophilic airway inflammation. S100A8, S100A9 and S100A12 are highly abundant proteins released by neutrophils and have been identified as important biomarkers in many inflammatory diseases. Herein, we report a new role for S100A8, S100A9 and S100A12 for producing MUC5AC, a major mucin protein in the respiratory tract. All three S100 proteins induced MUC5AC mRNA and the protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells in a dose-dependent manner. A Toll-like receptor 4 (TLR4) inhibitor almost completely abolished MUC5AC expression by all three S100 proteins, while neutralization of the receptor for advanced glycation end-products (RAGE) inhibited only S100A12-mediated production of MUC5AC. The S100 protein-mediated production of MUC5AC was inhibited by the pharmacological agents that block prominent signalling molecules for MUC5AC expression, such as mitogen-activated protein kinases, nuclear factor-κB (NF-κB) and epidermal growth factor receptor. S100A8, S100A9 and S100A12 equally elicited both phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear translocation of NF-κB/degradation of cytosolic IκB with similar kinetics through TLR4. In contrast, S100A12 preferentially activated the ERK pathway rather than the NF-κB pathway through RAGE. Collectively, these data reveal the capacity of these three S100 proteins to induce MUC5AC production in airway epithelial cells, suggesting that they all serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction.

  • MUC5AC expression through bidirectional communication of notch and epidermal growth factor receptor pathways
    Journal of Immunology, 2011
    Co-Authors: Jin Hyun Kang, Sung Woo Park, Il Yup Chung
    Abstract:

    Hyperproduction of goblet cells and mucin in the airway epithelium is an important feature of airway inflammatory diseases. We investigated the involvement of Notch signaling in MUC5AC expression in NCI-H292 cells, a human lung carcinoma cell line. Epidermal growth factor (EGF) stimulated generation of the Notch intracellular domain (NICD) in a RBP-Jκ–dependent manner. Treatment with γ-secretase inhibitors L-685,458 or DAPT or introduction of small interfering RNA directed against Notch1 reduced EGF-induced MUC5AC expression. The inhibitory effect of L-685,458 on EGF-induced MUC5AC mRNA and protein expression was also observed in primary human bronchial epithelial cells. Blockage of Notch signaling with L-685,458 or Notch siRNA resulted in a decrease in EGF-induced phosphorylation of ERK. These results suggested that ERK activation is necessary for the regulation of EGF receptor (EGFR)–mediated MUC5AC expression by Notch signaling. Conversely, forced expression of NICD induced both EGFR and ERK phosphorylation with MUC5AC expression even in the absence of EGF. Treatment of the NICD-expressing cells with EGF further augmented ERK phosphorylation in an additive manner. The ERK phosphorylation induced by exogenous NICD was inhibited by treatment with an Ab that antagonizes EGFR activity as well as by inhibitors of EGFR and ERK, implying that Notch signaling induces MUC5AC expression by activating the EGFR pathway. Collectively, these results suggest that MUC5AC expression is regulated by a bidirectional circuit between Notch and EGFR signaling pathways.

Kensei Komatsu - One of the best experts on this subject based on the ideXlab platform.

  • 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
    Journal of Biological Chemistry, 2012
    Co-Authors: Kensei Komatsu, Hirofumi Jono, John Z Zhang, Haidong Xu, Jiandong Li
    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.

  • 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
    Journal of Biological Chemistry, 2012
    Co-Authors: Jiyun Lee, Kensei Komatsu, Hirofumi Jono, John Z Zhang, Byungcheol Lee, Jae Hyang Lim, Hirofumi Kai, Chen Yan
    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. Background: Mucus overproduction is a hallmark of otitis media (OM) induced by Streptococcus pneumoniae. Results: PDE4B mediates S. pneumoniae-induced MUC5AC up-regulation by inhibiting the expression of a negative regulator MKP-1. Conclusion: PDE4-specific inhibitor rolipram inhibits S. pneumoniae-induced MUC5AC up-regulation. Significance: Identifying PDE4B as a molecular target for inhibiting MUC5AC by up-regulating MKP-1 may have significant therapeutic potential for treating OM.