CREB Mediates Prostaglandin F2α-Induced MUC5AC Overexpression

Abstract

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 PGE2 and PGF2α. PGE2-induced mucin production has been well studied, but the effect of PGF2α on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF2α on MUC5AC production, we investigated the signal transduction of PGF2α associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF2α induces MUC5AC overproduction via a signaling cascade involving protein kinase C, ERK, p90 ribosomal S6 protein kinase, and CREB. The regulation of PGF2α-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 PGF2α receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE2 and other inflammatory mediators, our findings have important clinical implications for the management of airway mucus hypersecretion.