Abstract
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.
Highlights
Mucus secretion in the airway, including the nasal and paranasal sinus cavities, is drained by the mucociliary transport system [1]
We showed that Hematopoietic PGD2 synthase (H-PGDS) expression was characteristic of nasal polyp tissues with a high secretion of prostaglandin D2 (PGD2)
D prostanoid receptor 1 (DP1) Receptor Is Involved in PGD2-induced MUC5B Expression—we examined the role of PGD2 receptors in the signal transduction pathway leading to MUC5B gene expression in airway epithelial cells by transfecting NCI-H292 cells with 50 nM small Interfering RNA (siRNA) against DP1 or CRTH2
Summary
Mucus secretion in the airway, including the nasal and paranasal sinus cavities, is drained by the mucociliary transport system [1]. Our results showed a critical role of extracellular signal-regulated kinase (ERK1/2) mitogen-activated protein kinase (MAPK) in PGD2induced MUC5B gene expression in airway epithelial cells. To investigate whether PGD2 induced MUC5B gene expression in a time-dependent manner, we performed RT-PCR after treating NCI-H292 cells with 1 M PGD2 for various times (1, 3, 6, 12, and 24 h).
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