title: Mechanisms of diarrhea in the interleukin-2-deficient mouse model of colonic inflammation.
abstract: Colitis in interleukin-2-deficient (IL-2(-/-)) mice resembles ulcerative colitis in humans. We studied epithelial transport and barrier function in IL-2(-/-) mice and used this model to characterize mechanisms of diarrhea during intestinal inflammation. (22)Na(+) and (36)Cl(-) fluxes were measured in proximal colon. Net Na(+) flux was reduced from 4.0 +/- 0.5 to 0.8 +/- 0.5 micromol.h(-1).cm(-2), which was paralleled by diminished mRNA and protein expression of the Na(+)/H(+) exchanger NHE3. Net Cl(-) flux was also decreased from 2.2 +/- 1.6 to -2.7 +/- 0.6 micromol.h(-1).cm(-2), indicating impaired Na(+)-Cl(-) absorption. In distal colon, aldosterone-induced electrogenic Na(+) absorption was 6.1 +/- 0.9 micromol.h(-1).cm(-2) in controls and was abolished in IL-2(-/-) mice. Concomitantly, mRNA expression of beta- and gamma-subunits of the epithelial sodium channel (ENaC) was reduced. Epithelial barrier was studied in proximal colon by impedance technique and mannitol fluxes. In contrast to ulcerative colitis, epithelial resistance was increased and mannitol fluxes were decreased in IL-2(-/-) mice. This was in accord with the findings of reduced ion transport as well as increased expression of tight junction proteins occludin and claudin-1, -2, -3, and -5. In conclusion, the IL-2(-/-) mucosa exhibits impaired electroneutral Na(+)-Cl(-) absorption and electrogenic Na(+) transport due to reduced mRNA and protein expression of NHE3 and ENaC beta- and gamma-subunit mRNA. This represents a model of early intestinal inflammation with absorptive dysfunction due to impaired transport protein expression/function while epithelial barrier is still intact. Therefore, this model is ideal to study regulation of transporter expression independent of barrier defects.
authors.affiliation: Department of Gastroenterology, Charité-University Medicine Berlin, 12200 Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Barmeyer
authors.forename: M
authors.initials: M
authors.lastname: Harren
authors.forename: H
authors.initials: H
authors.lastname: Schmitz
authors.forename: U
authors.initials: U
authors.lastname: Heinzel-Pleines
authors.forename: J
authors.initials: J
authors.lastname: Mankertz
authors.forename: U
authors.initials: U
authors.lastname: Seidler
authors.forename: I
authors.initials: I
authors.lastname: Horak
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: M
authors.initials: M
authors.lastname: Fromm
authors.forename: J D
authors.initials: JD
authors.lastname: Schulzke
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002712:Chlorides / Q000378:metabolism; D003092:Colitis / Q000150:complications* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003967:Diarrhea / Q000209:etiology*; D017097:Electric Impedance; D004594:Electrophysiology; D053503:Epithelial Sodium Channels; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics; D007408:Intestinal Absorption; D008353:Mannitol / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D062793:Occludin; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D002712:Chlorides; D053503:Epithelial Sodium Channels; D007376:Interleukin-2; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; C000613385:SLC9A3 protein, human; C507049:Scnn1b protein, mouse; C000613386:Slc9a3 protein, mouse; D015222:Sodium Channels; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D008353:Mannitol; D012964:Sodium