Abstract
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 γ (IFNγ) down-regulated CFTR expression in epithelial cells (T84), but by contrast, we found that IFNγ up-regulated CFTR mRNA and protein expression in rat and human mast cells. IFNγ 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 IFNγ-mediated down-regulation of CFTR was JAK2-dependent and ERK- and p38-independent. Furthermore, IFNγ 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, IFNγ 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 IFNγ-mediated inhibition of mediator secretion. This and other work suggests that the effect of IFNγ on CFTR expression in mast cells is important for their function.
Footnotes
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This work was funded by grants to A.D.B. from the Canadian Institutes of Health Research (CIHR) and to M.D. from the Canadian Cystic Fibrosis Foundation. M.K. was supported by a student voucher from CIHR.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.087528.
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ABBREVIATIONS: CFTR, cystic fibrosis transmembrane conductance regulator; PMC, rat peritoneal mast cell(s); ClC, voltage-gated Cl- channel; IFN, interferon; JAK, Janus tyrosine kinase; STAT, signal transduction and activator of transcription; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; TNF, tumor necrosis factor; AG-490, α-cyano-(3,4-dihydroxy)-N-benzylcinnamide tyrphostin B42; SB202190, C20H14FN3O; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene); PMA, phorbol 12-myristate 13-acetate; HTB, HEPES Tyrode's buffer; MC, mast cell; RCMC, rat cultured mast cell(s); FBS, fetal bovine serum; LAD2, Laboratory of Allergic Diseases mast cell line 2; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; JNK, c-Jun NH2-terminal kinase; FAM, 6-carboxyfluorescein; BSA, bovine serum albumin; PCR, polymerase chain reaction; MQAE, N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide; IL, interleukin.
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↵1 Current address: Allergy-Immunology Division, Feinberg School of Medicine, Northwestern University, Chicago, IL.
- Received April 5, 2005.
- Accepted July 26, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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Differential Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by Interferon γ in Mast Cells and Epithelial Cells
