In vivo evidence for interferon-gamma-mediated homeostatic mechanisms in small intestine of the NHE3 Na+/H+ exchanger knockout model of congenital diarrhea.
Mice lacking NHE3, the major absorptive Na(+)/H(+) exchanger in the intestine, are the only animal model of congenital diarrhea. To identify molecular changes underlying compensatory mechanisms activated in chronic diarrheas, cDNA microarrays and Northern blot analyses were used to compare global mRNA expression patterns in small intestine of NHE3-deficient and wild-type mice. Among the genes identified were members of the RegIII family of growth factors, which may contribute to the increased absorptive area, and a large number of interferon-gamma-responsive genes. The latter finding is of particular interest, since interferon-gamma has been shown to regulate ion transporter activities in intestinal epithelial cells. Serum interferon-gamma was elevated 5-fold in NHE3-deficient mice; however, there was no evidence of inflammation, and unlike conditions such as inflammatory bowel disease, levels of other cytokines were unchanged. In addition, quantitative PCR analysis showed that up-regulation of interferon-gamma mRNA was localized to the small intestine and did not occur in the colon, spleen, or kidney. These in vivo data suggest that elevated interferon-gamma, produced by gut-associated lymphoid tissue in the small intestine, is part of a homeostatic mechanism that is activated in response to the intestinal absorptive defect in order to regulate the fluidity of the intestinal tract.
Woo
Alison L
AL
Department of Molecular Genetics, University of Cincinnati College of Medicine, Ohio 45267-0524, USA.
Gildea
Lucy A
LA
Tack
Leslie M
LM
Miller
Marian L
ML
Spicer
Zachary
Z
Millhorn
David E
DE
Finkelman
Fred D
FD
Hassett
Daniel J
DJ
Shull
Gary E
GE
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003967:Diarrhea / Q000151:congenital / Q000235:genetics / Q000503:physiopathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D007371:Interferon-gamma / Q000097:blood / Q000502:physiology*; D007421:Intestine, Small / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D012333:RNA, Messenger; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D007371:Interferon-gamma