IL-4 and IL-13 up-regulate intestinal trefoil factor expression: requirement for STAT6 and de novo protein synthesis.
The development of intestinal goblet cell hyperplasia/hypertrophy during nematode infection involves the Th2 cytokines IL-4 and IL-13 via STAT6 activation. This is thought to play an important role in host protective immunity against the infection. In this study we demonstrate that IL-4 and IL-13 up-regulate the specific goblet cell product trefoil factor-3 (TFF3) from the mucus-producing HT-29 CL.16E and HT-29 cells selected by adaptation to methotrexate. Up-regulation of TFF3 mRNA and protein levels occurred in a time- and dose-dependent fashion and was accompanied by up-regulation of the goblet cell product mucin 2 (MUC2). Addition of actinomycin D before IL-4/IL-13 stimulation led to decreases in TFF3 mRNA levels similar to those observed in controls without IL-4/IL-13. Furthermore, IL-4-mediated increased TFF3 transcription required de novo protein synthesis. Stable transfection of HT-29 CL.16E cells with a truncated dominant-negative form of STAT6 produced a cell line that was unresponsive to IL-4/IL-13. Although only one consensus STAT6 binding site is contained in the TFF3 gene, located in the intron 1, it did not operate as an enhancer in the context of an SV40 promoter/luciferase construct. Thus, STAT6 activation mediates a transcriptional enhancement of TFF3 by induction of de novo synthesized protein in goblet cells.
Institut National de la Santé et de la Recherche Médicale, Unité 45, Faculté de Médecine RTH Laennec, Lyon, France.
Carine
C
Blanchard
Stéphane
S
Durual
Monique
M
Estienne
Karim
K
Bouzakri
Markus H
MH
Heim
Nikolaus
N
Blin
Jean-Claude
JC
Cuber
D020397:Goblet Cells / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000378:metabolism / Q000502:physiology*; D009077:Mucins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009479:Neuropeptides; D010455:Peptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D014176:Protein Biosynthesis; D018123:Receptors, Interleukin / Q000032:analysis; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000032:analysis; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D015854:Up-Regulation / Q000276:immunology*
C508181:IL13RA1 protein, human; C508185:Il13ra1 protein, rat; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C082495:TFF3 protein, human; C099037:TFF3 protein, rat; D015534:Trans-Activators; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases