CREB mediates prostaglandin F2alpha-induced MUC5AC overexpression.
Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are PGE(2) and PGF(2alpha). PGE(2)-induced mucin production has been well studied, but the effect of PGF(2alpha) on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF(2alpha) on MUC5AC production, we investigated the signal transduction of PGF(2alpha) associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF(2alpha) induces MUC5AC overproduction via a signaling cascade involving protein kinase C, ERK, p90 ribosomal S6 protein kinase, and CREB. The regulation of PGF(2alpha)-induced MUC5AC expression by CREB was further confirmed by cAMP response element-dependent MUC5AC promoter activity and by interaction between CREB and MUC5AC promoter. The abrogation of all downstream signaling activities via suppression of each signaling molecule along the pathway indicates that a single pathway from PGF(2alpha) receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE(2) and other inflammatory mediators, our findings have important clinical implications for the management of airway mucus hypersecretion.
Chung
Wen-Cheng
WC
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Ryu
Seung-Hee
SH
Sun
Hongxia
H
Zeldin
Darryl C
DC
Koo
Ja Seok
JS
D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism*; D015237:Dinoprost / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D015237:Dinoprost