Differential regulation of cystic fibrosis transmembrane conductance regulator by interferon gamma in mast cells and epithelial cells.
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 (IFNgamma) down-regulated CFTR expression in epithelial cells (T84), but by contrast, we found that IFNgamma up-regulated CFTR mRNA and protein expression in rat and human mast cells. IFNgamma 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 IFNgamma-mediated down-regulation of CFTR was JAK2-dependent and ERK- and p38-independent. Furthermore, IFNgamma 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, IFNgamma 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 IFNgamma-mediated inhibition of mediator secretion. This and other work suggests that the effect of IFNgamma on CFTR expression in mast cells is important for their function.
Kulka
Marianna
M
Pulmonary Research Group, University of Alberta, Edmonton, Canada.
Dery
Rene
R
Nahirney
Drew
D
Duszyk
Marek
M
Befus
A Dean
AD
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009559:Nippostrongylus / Q000276:immunology; D011804:Quinolines; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D002712:Chlorides; D004791:Enzyme Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; C078229:N-(6-methoxyquinolyl)acetoethyl ester; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007073:Immunoglobulin E; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases