We examined the in vivo effects of agonists for prostaglandin E2 receptors (EP1, EP2, EP3, and EP4) on mucus hypersecretion. We also examined the in vitro effects of EP agonists on airway epithelial cells.
Methods:
For the in vivo study, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. For the in vitro study, we used NCI-H292 cells and cultured human nasal epithelial cells.
Results:
Subcutaneous injection of the EP4 agonist (1 to 100 μg/kg) dose-dependently inhibited LPS-induced mucus production and neutrophil infiltration. The EP3 agonist (100 μg/kg) also had some inhibitory effects on mucus production, whereas the EP1 and EP2 agonists showed no effect. The LPS-induced mucus secretion was significantly inhibited by the EP3 and EP4 agonists at 10−6 mol/L in cultured epithelial cells. The LPS-induced interleukin-8 secretion was also inhibited by the EP3 and EP4 agonists.
Conclusions:
These results indicate that the EP4 agonist inhibited LPS-induced airway mucus hypersecretion directly or indirectly through the suppression of interleukin-8 secretion and neutrophil infiltration.
PuginJSchurer-MalyCCLeturcqDMoriartyAUlevitchRJTobiasPS. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A1993;90:2744–8.
2.
HailmanEVasselonTKelleyM. Stimulation of macrophages and neutrophils by complexes of lipopolysaccharide and soluble CD14. J Immunol1996;156:4384–90.
3.
ChowJCYoungDWGolenbockDTChristWJGusovskyF. Toll-like receptor—4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem1999;274:10689–92.
4.
GonYAsaiYHashimotoS. A20 inhibits toll-like receptor 2– and 4–mediated interleukin-8 synthesis in airway epithelial cells. Am J Respir Cell Mol Biol2004;31:330–6.
5.
SmirnovaMGGuoLBirchallJPPearsonJP. LPS upregulates mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells. Cell Immunol2003;221:42–9.
6.
IkegamiRSugimotoYSegiE. The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by lipopolysaccharide in C3H/HeN peritoneal macrophages. J Immunol2001;166:4689–96.
7.
TakayamaKGarcía-CardenaGSukhovaGKComanderJGimbroneMAJrLibbyP. Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem2002;277:44147–54.
8.
YamaneHSugimotoYTanakaSIchikawaA. Prostaglandin E2 receptors, EP2 and EP4, differentially modulate TNF-alpha and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils. Biochem Biophys Res Commun2000;278:224–48.
9.
VassiliouEJingHGaneaD. Prostaglandin E2 inhibits TNF production in murine bone marrow-derived dendritic cells. Cell Immunol2003;223:120–32.
10.
JingHVassiliouEGaneaD. Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells. J Leukoc Biol2003;74:868–79.
11.
NarumiyaSSugimotoYUshikubiF. Prostanoid receptors: Structures, properties, and functions. Physiol Rev1999;79:1193–226.
12.
KishiokaCShimizuTFujitaKItoYMajimaYSakakuraY. Monoclonal antibody-detectable carbohydrate epitopes of human nasal secretions are differentially expressed in tissue and diseases. Am J Rhinol1999;13:37–43.
13.
ShimizuTTakahashiYKawaguchiSSakakuraY. Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. Am J Respir Crit Care Med1996;153:1412–8.
14.
UsuiSShimizuTKishiokaCFujitaKSakakuraY. Secretory cell differentiation and mucus secretion in cultures of human nasal epithelial cells: Use of a monoclonal antibody to study human nasal mucin. Ann Otol Rhinol Laryngol2000;109:271–7.
15.
ShimizuTShimizuSHattoriRGabazzaECMajimaY. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med2003;168:581–7.
16.
ArmstrongRA. Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils. Br J Pharmacol1995;116:2903–8.
17.
de MoraesVL GoncalvesVargaftigB BorisLefortJMeagerAChignardM. Effect of cyclo-oxygenase inhibitors and modulators of cyclic AMP formation on lipopolysaccharide-induced neutrophil infiltration in mouse lung. Br J Pharmacol1996;117:1792–6.
18.
NoguchiKIwasakiKShitashigeM. Downregulation of lipopolysaccharide-induced intercellular adhesion molecule-1 expression via EP2/EP4 receptors by prostaglandin E2 in human fibroblasts. Inflammation2001;25:75–81.
19.
ShimizuTHiranoHMajimaYSakakuraY. A mechanism of antigen-induced mucus production in nasal epithelium of sensitized rats. A comparison with lipopolysaccharide-induced mucus production. Am J Respir Crit Care Med2000;161:1648–54.
20.
ShimizuTTakahashiYTakeuchiKMajimaYSakakuraY. Role of neutrophil elastase in endotoxin-induced mucus hypersecretion in rat nasal epithelium. Ann Otol Rhinol Laryngol2000;109:1049–54.
21.
KimYDKwonEJParkDWSongSYYoonSKBaekSH. Interleukin-1beta induces MUC2 and MUC5AC synthesis through cyclooxygenase-2 in NCI-H292 cells. Mol Pharmacol2002;62:1112–8.
22.
GrayTNettesheimPLoftinC. Interleukin-1beta-induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E2 receptors, and cyclic AMP-protein kinase A signaling. Mol Pharmacol2004;66:337–46.
23.
LemieuxLIRahalSSKennedyCR. PGE2 reduces arachidonic acid release in murine podocytes: Evidence for an autocrine feedback loop. Am J Physiol Cell Physiol2003;284:C302–C309.
24.
KunikataTYamaneHSegiE. Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3. Nat Immunol2005;6:524–31.
25.
KasaiKSatoSSuzukiK. A novel prostaglandin E receptor subtype agonist, ONO-4819, attenuates acute experimental liver injury in rats. Hepatol Res2001;21:252–60.
