Leukotriene D4 upregulates MUC2 gene transcription in human epithelial cells.
OBJECTIVE
Leukotriene (LT) D(4) has been shown to induce mucus secretion in the airways. Excessive mucus secretion characterizes airway inflammatory disease such as asthma, allergic rhinitis. However, little is known about the effect of LTD(4) on mucin gene expression. The aim of this study was to investigate the effect of LTD(4) on MUC2 gene expression in cultured epithelial cells (HM3-MUC2 cells).


METHODS
HM3-MUC2 cells were treated with LTD(4) for 2 or 6 h. Reporter gene assay was mainly used for analysis.MUC2 protein levels were measured using an enzyme-linked immunosorbent assay.


RESULTS
LTD(4) significantly increased MUC2 gene transcriptional activity in a dose-dependent manner. Pranlukast, which is a selective antagonist of CysLT(1) receptor, inhibited LTD(4)-induced MUC2 gene transcriptional activity in a dose-dependent manner. LTD(4)-induced MUC2 gene transcriptional activity was also suppressed by a G-protein inhibitor (pertussis toxin),a protein kinase C (PKC) inhibitor (bisindolylmaleimide), a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059), an extracellular signal regulated kinase-2 (ERK-2) inhibitor (AG126) and a nuclear factor kappaB (NF-kappaB) inhibitor. In addition, pranlukast inhibited LTD(4)-induced NF-kappaB activity.


CONCLUSIONS
These results suggest that LTD(4 )upregulates MUC2 gene transcription via a signaling pathway involving CysLT(1) receptor, G-protein, PKC, MEK, ERK and NF-kappaB.
Suzuki
Shinya
S
Department of Otorhinolaryngology, Head and Neck Surgery, Mie University Graduate School of Medicine, Edobashi, Tsu, Mie, Japan.
Takeuchi
Kazuhiko
K
Ishinaga
Hajime
H
Basbaum
Carol
C
Majima
Yuichi
Y
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D017998:Leukotriene D4 / Q000008:administration & dosage / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D055262:Mucin-2; D009077:Mucins / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
C524625:MUC2 protein, human; D008565:Membrane Proteins; D055262:Mucin-2; D009077:Mucins; D016328:NF-kappa B; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; C083169:leukotriene D4 receptor