Differential regulation of airway mucin gene expression and mucin secretion by extracellular nucleotide triphosphates

The effects of extracellular nucleotide triphosphates on the stimulation of mucin production by airway epithelial cells were examined. The order of po tency in stimulating mucin secretion in primary cultures of human tracheobr onchial epithelial cells is: uridine 5'-triphosphate (UTP) approximate to a denosine 5'-triphosphate (ATP) approximate to ATP-gamma -S > uridine 5'-dip hosphate approximate to adenosine 5'-diphosphate > alpha,beta -methylene AT P much greater than adenosine. However, only UTP can increase mucin gene (M UC5AC, MUC5B) expression; ATP and other analogues have no stimulatory effec t. The stimulation of MUC5AC and MUC5B expression by UTP is time- and dose- dependent. A similar effect on the elevation of mucous cell population in m ouse airway epithelium can be demonstrated in vivo by an intratracheal inst illation of UTP-saline solution. The stimulatory effect of UTP or ATP on mu cin secretion was inhibited by pertussis toxin, U73122, and Calphostin C, b ut not by PD98059, suggesting a G-protein/phospholipase (PQ C/protein kinas e (PK) C-dependent and mitogen-activated protein kinase (MAPK)-independent signaling pathway. However, the stimulatory effect of UTP on mucin gene exp ression was sensitive to pertussis toxin and PD98059, but not to Calphostin C and U73122, suggesting a G-protein/MAPK-dependent and PLC/PKC-independen t signaling pathway. These findings are the first demonstration that UTP, a pyrimidine nucleotide triphosphate, can enhance both mucin secretion and m ucin gene expression through different signaling pathways.