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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 28, 2005; DOI: 10.1124/jpet.105.087528

0022-3565/05/3152-563-570$20.00
JPET 315:563-570, 2005
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CELLULAR AND MOLECULAR

Differential Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by Interferon {gamma} in Mast Cells and Epithelial Cells

Marianna Kulka1, Rene Dery, Drew Nahirney, Marek Duszyk, and A. Dean Befus

Pulmonary Research Group, University of Alberta, Edmonton, Alberta, Canada

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride channel in epithelial cells; recently, we identified it in mast cells. Previous work that we confirmed showed that interferon {gamma} (IFN{gamma}) down-regulated CFTR expression in epithelial cells (T84), but by contrast, we found that IFN{gamma} up-regulated CFTR mRNA and protein expression in rat and human mast cells. IFN{gamma} up-regulation of CFTR in mast cells was inhibited by p38 and extracellular signal-regulated kinase (ERK) kinase inhibitors but not a Janus tyrosine kinase (JAK)2 inhibitor, whereas in T84 cells IFN{gamma}-mediated down-regulation of CFTR was JAK2-dependent and ERK- and p38-independent. Furthermore, IFN{gamma} down-regulation of CFTR in T84 epithelial cells was STAT1-dependent, but up-regulation of CFTR in mast cells was STAT1-independent. Thus, differential regulatory pathways of CFTR expression in mast cells and epithelial cells exist that depend upon either p38/ERK or JAK/STAT pathways, respectively. Surprisingly, IFN{gamma} treatment of mast cells inhibited Cl- efflux, in contrast to up-regulation of CFTR/mRNA and protein expression. However, down-regulation of Cl- flux correlated with IFN{gamma}-mediated inhibition of mediator secretion. This and other work suggests that the effect of IFN{gamma} on CFTR expression in mast cells is important for their function.

Received April 5, 2005; accepted July 26, 2005.

Address correspondence to: Dr. A. Dean Befus, Room 550A HMRC, Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada, T6G 2S2. E-mail: dean.befus{at}ualberta.ca






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