LPS-stimulated MUC5AC production involves Rac1-dependent MMP-9 secretion and activation in NCI-H292 cells

Binker, Marcelo Gustavo; Binker-Cosen, Andres A.; Richards, Daniel A.; Oliver, Brenda; Cosen-Binker, Laura Iris

doi:10.1016/j.bbrc.2009.05.136

Cited by 34 publications

(34 citation statements)

References 28 publications

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“…In addition to other MAPKs, the ERK MAPK has been shown to modulate MMP expression (12). Inhibition of ROS by flavoenzyme inhibitors or antioxidants has been shown to decrease MMP expression (8,14,15).…”

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

“…Its role in mediating ROS generation has been implicated in many disease processes, including fibrosis (17)(18)20). Studies in which Rac1 has been shown to regulate MMP production via increased ROS were performed in non-phagocytic cells, such as fibroblasts, epithelial cells, and adenocarcinoma cells, and reduction of ROS decreased MMP expression and activity (14,15,21,22). However, the molecular mechanism(s) by which Rac1 modulates MMP-9 gene transcription, and the basis of these actions in phagocytic cells has not been demonstrated.…”

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

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Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

Murthy

Ryan

et al. 2010

Journal of Biological Chemistry

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Aberrant matrix deposition is a hallmark of pulmonary fibrosis and is characterized by an imbalance between matrix deposition and degradation. We have previously shown that mice harboring a conditional deletion of the GTP-binding protein, Rac1, in macrophages are protected from asbestos-induced pulmonary fibrosis. To investigate the contribution of aberrant matrix degradation, we addressed the role of Rac1 in regulating expression of macrophage-specific MMP-9 (matrix metalloproteinase-9). We found that MMP-9 gene transcription was significantly greater in Rac1 null macrophages. Deletion and mutational analysis of the MMP-9 promoter revealed that both SP-1 and AP-1 are essential for MMP-9 transcription. Overexpression of constitutive active Rac1 (V12) revealed that H 2 O 2 was derived from the mitochondria. Rac1-induced H 2 O 2 generation down-regulated MMP-9 gene transcription, whereas catalase overexpression in WT cells enhanced MMP-9 expression. SP-1 interacted directly with both c-Jun and c-Fos, and H 2 O 2 decreased this binding, suggesting that SP-1 and AP-1 function cooperatively to regulate MMP-9 transcription. Rac1-mediated H 2 O 2 inhibited the ERK MAPK, which was essential for activation of SP-1 and AP-1. ERK activation and MMP-9 expression were recovered by overexpressing catalase or transfecting siRNA for the mitochondrial iron-sulfur protein, Rieske. These observations were recapitulated in vivo. MMP-9 mRNA was higher in alveolar macrophages isolated from Rac1 null mice and wild type mice given catalase. Rac1 regulates MMP-9 transcription via mitochondrial H 2 O 2 generation, providing a potential mechanism by which Rac1 null mice fail to develop pulmonary fibrosis.

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Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

Murthy

Ryan

et al. 2010

Journal of Biological Chemistry

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“…Several classes of inflammatory mediators have been implicated in the process of mucus hypersecretion based on their ability to stimulate secretion from cultured cells and tissue explants (5). These inflammatory mediators are lipopolysaccharides (6), reactive oxygen species (7), and arachidonic acid metabolites (8,9).…”

Section: Mucin Gene Expression Can Be Affected By Inflammatory Mediatmentioning

confidence: 99%

“…To determine whether PGD 2 could induce mucin gene expression in NHNE and NCI-H292 cells, we performed real-time quantitative PCR on cells that had been treated with various concentrations of PGD 2 (0.01, 0.1, and 1 M) for 24 h. The mRNA levels of secreted mucin genes in the cell lysates, such as MUC5B, 6,8, and 5AC, were determined and compared using RT-PCR (data not shown). Mucin gene expression was significantly induced by 0.01 M PGD 2 .…”

Section: Pgd 2 Induces Muc5b Expression In Both Nhne Cells and Human mentioning

confidence: 99%

“…To investigate whether PGD 2 induced MUC5B gene expression in a time-dependent manner, we performed RT-PCR after treating NCI-H292 cells with 1 M PGD 2 for various times (1,3,6,12, and 24 h). We observed a time-dependent increase in expression of MUC5B in NCI-H292 cells over a 24-h time period (greater than 2-fold increase) (Fig.…”

Section: Pgd 2 Induces Muc5b Expression In Both Nhne Cells and Human mentioning

confidence: 99%

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The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

Choi

Lee

Aoyagi

et al. 2011

Journal of Biological Chemistry

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Mucus hypersecretion is a prominent feature of respiratory diseases, and MUC5B is a major airway mucin. Mucin gene expression can be affected by inflammatory mediators, including prostaglandin (PG) D 2, an inflammatory mediator synthesized by hematopoietic PGD synthase (H-PGDS). PGD 2 binds to either D-prostanoid receptor (DP1) or chemoattractant receptor homologous molecule expressed on T-helper type 2 cells (CRTH2). We investigated the mechanisms by which PGD 2 induces MUC5B gene expression in airway epithelial cells. Western blot analysis showed that H-PGDS was highly expressed in nasal polyps. Similar results were obtained for PGD 2 expression. In addition, we could clearly detect the expressions of both H-PGDS and DP1 in nasal epithelial cells but not CRTH2. We demonstrated that PGD 2 increased MUC5B gene expression in normal human nasal epithelial cells as well as in NCI-H292 cells in vitro. S5751, a DP1 antagonist, inhibited PGD 2 -induced MUC5B expression, whereas a CRTH2 antagonist (OC0459) did not. These data suggest that PGD 2 induced MUC5B expression via DP1. Pretreatment with extracellular signal-regulated kinase (ERK) inhibitor (PD98059) blocked both PGD 2 -induced ERK mitogen-activated protein kinase (MAPK) activation and MUC5B expression. Proximity ligation assays showed direct interaction between RSK1 and cAMP response element-binding protein (CREB). Stimulation with PGD 2 caused an increase in intracellular cAMP levels, whereas intracellular Ca 2؉ did not have such an effect. PGD 2 -induced MUC5B mRNA levels were regulated by CREB via direct interaction with two cAMP-response element sites (؊921/؊914 and ؊900/؊893). Finally, we demonstrated that PGD 2 can induce MUC5B overproduction via ERK MAPK/ RSK1/CREB signaling and that DP1 receptor may have suppressive effects in controlling MUC5B overproduction in the airway.Mucus secretion in the airway, including the nasal and paranasal sinus cavities, is drained by the mucociliary transport system (1). Normal mucus secretion is essential for survival (2), but upregulation of mucin gene expression is a major manifestation of chronic airway diseases such as allergic rhinitis, asthma, and cystic fibrosis (3, 4). Patients suffering from these diseases have pathological abnormalities in both the submucosal glands and surface epithelium, characterized by inflammation, increased mucus cell number, and increased airway mucus. Several classes of inflammatory mediators have been implicated in the process of mucus hypersecretion based on their ability to stimulate secretion from cultured cells and tissue explants (5). These inflammatory mediators are lipopolysaccharides (6), reactive oxygen species (7), and arachidonic acid metabolites (8, 9).A total of 20 different mucin genes have been identified and subdivided into two groups, membrane-bound and secreted mucins, according to Human Genome Mapping conventions. The secreted mucins are MUC5AC, MUC5B, MUC6, and MUC19 (10 -13). Mucins are primarily synthesized by two different cell types in the airway tract, namely...

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Lixisenatide ameliorated lipopolysaccharide (LPS)‐induced expression of mucin and inflammation in bronchial epithelial cells

Xu,

Chen,

Zhang

et al. 2023

J Biochem & Molecular Tox

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Chronic obstructive pulmonary disease (COPD) induces serious social and economic burdens due to its high disability and mortality, the pathogenesis of which is highly involved with inflammation, oxidative stress (OS), and mechanism of mucin 5AC (MUC5AC) secretion. Lixisenatide is a selective glucagon‐like peptide 1 receptor agonist recently reported to have anti‐inflammatory properties. Our study will focus on the potential impact of lixisenatide on lipopolysaccharide (LPS)‐induced mucin secretion and inflammation in 16 human bronchial epithelial (16HBE) cells to check its potential function in COPD. 16HBE cells were treated with LPS, with or without lixisenatide (10 and 20 nM) for 1 day. Remarkably declined cell viability, enhanced lactate dehydrogenase release, activated OS, and elevated release of inflammatory cytokines were observed in LPS‐treated 16HBE cells, accompanied by the activation of nuclear factor‐κB signaling, all of which were signally reversed by lixisenatide. Moreover, elevated expression and release of MUC5AC were observed in LPS‐treated 16HBE cells but were markedly repressed by lixisenatide. Furthermore, the repressed nuclear factor erythroid 2‐related factor 2 (Nrf2) level in LPS‐treated 16HBE cells was notably rescued by lixisenatide. Lastly, following the knockdown of Nrf2, the protective function of lixisenatide on LPS‐triggered MUC5AC release in 16HBE cells was significantly abrogated. Collectively, lixisenatide ameliorated LPS‐induced expression of mucin and inflammation in bronchial epithelial cells by regulating Nrf2.

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LPS-stimulated MUC5AC production involves Rac1-dependent MMP-9 secretion and activation in NCI-H292 cells

Cited by 34 publications

References 28 publications

Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

Lixisenatide ameliorated lipopolysaccharide (LPS)‐induced expression of mucin and inflammation in bronchial epithelial cells

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