Interleukin-1beta regulates CFTR expression in human intestinal T84 cells.
Cystic fibrosis is an autosomal recessive genetic disease, produced by a mutation in the CFTR gene that impairs its function as a chloride channel. In this work, we have examined the effects of interleukin-1beta (IL-1beta) on the expression of CFTR in human colonic T84 cells. Treatment of T84 cells with IL-1beta (0.25 ng/ml) for 4 h resulted in an increased CFTR expression (mRNA and protein). However, higher doses of IL-1beta (1 ng/ml and over) produced inhibition of CFTR mRNA and protein expression. The protein kinase C (PKC) inhibitors H7 (50 microM) and GF109203X (1 microM) inhibited the stimulatory effect of IL-1beta. Similar effects were seen in the presence of the protein tyrosine kinase (PTK) inhibitors genistein (60 microM) and herbymicin A (2 microM). These results suggest that some PKC isoform(s) and at least a PTK might be involved in the CFTR up-regulation induced by IL-1beta. The repression of CFTR up-regulation by cycloheximide (35.5 microM) suggests the participation of a de novo synthesized protein. Results obtained by using the RNA polymerase II inhibitor DRB (78 microM), suggest that the increased mRNA levels seen after IL-1beta treatment are not due to an increased stability of the message. We conclude that the CFTR mRNA and protein levels are modulated by IL-1beta, this cytokine being the first extracellular protein known to up-regulate CFTR gene expression.
Cafferata
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EG
Instituto de Investigaciones Bioquímicas-Fundación Campomar (IIB, UBA, IIBBA, CONICET), Patricias Argentinas 435, 1405, Buenos Aires, Argentina.
González-Guerrico
A M
AM
Giordano
L
L
Pivetta
O H
OH
Santa-Coloma
T A
TA
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology; D016227:Benzoquinones; D002460:Cell Line; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D047029:Lactams, Macrocyclic; D008301:Maleimides / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
D016227:Benzoquinones; C505032:CFTR protein, human; D004791:Enzyme Inhibitors; D007211:Indoles; D007375:Interleukin-1; D047029:Lactams, Macrocyclic; D008301:Maleimides; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D011809:Quinones; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017828:Rifabutin; C020754:herbimycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003513:Cycloheximide; D019833:Genistein; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate