Prolonged interferon-gamma exposure decreases ion transport, NKCC1, and Na+-K+-ATPase expression in human intestinal xenografts in vivo.
IFN-gamma is elevated in intestinal inflammation and alters barrier and transport functions in human colonic epithelial cell lines, but its effects on normal human small intestinal epithelium in vivo are poorly defined. We investigated effects of prolonged IFN-gamma exposure on ion transport and expression of transporters by using human fetal small intestinal xenografts. Xenograft-bearing mice were injected with IFN-gamma, and 24 h later xenografts were harvested and mounted in Ussing chambers. Baseline potential difference (PD) was not affected by IFN-gamma treatment. However, conductance was enhanced and agonist-stimulated ion transport was decreased. IFN-gamma also decreased expression of the Na+-K+-2Cl- cotransporter and the alpha-subunit of Na+-K+-ATPase compared with controls, whereas levels of the calcium-activated Cl- channel and CFTR were unaltered. Thus prolonged exposure to IFN-gamma leads to decreased ion secretion due, in part, to decreased ion transporter levels. These findings demonstrate the implications of elevated IFN-gamma levels in human small intestine and validate the human intestinal xenograft as a model to study chronic effects of physiologically relevant stimuli.
Bertelsen
Lone S
LS
Division of Gastroenterology, Department of Medicine, University of California-San Diego School of Medicine, San Diego, California 92103-8414, USA.
Eckmann
Lars
L
Barrett
Kim E
KE
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation; D051379:Mice; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis*; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis*; D064506:Solute Carrier Family 12, Member 2; D013268:Stimulation, Chemical; D014183:Transplantation, Heterologous
C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D012333:RNA, Messenger; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007371:Interferon-gamma; D002217:Carbachol; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D015232:Dinoprostone; D002118:Calcium