In Vivo Evidence for Interferon-γ-mediated Homeostatic Mechanisms in Small Intestine of the NHE3 Na+/H+ Exchanger Knockout Model of Congenital Diarrhea

Woo, Alison L.; Gildea, Lucy A.; Tack, L. M.; Miller, Marian L.; Spicer, Zachary; Millhorn, David E.; Finkelman, Fred D.; Hassett, Daniel J.; Shull, Gary E.

doi:10.1074/jbc.m205288200

Cited by 43 publications

(33 citation statements)

References 80 publications

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“…4). Mucosal expression of IFN-␥, described originally in the small intestine of NHE3 Ϫ/Ϫ mice by Woo et al (33) and by our group (12), did not change in the distal colon of NHE3-deficient mice in either conventional or barrier environment (data not shown). Collectively, these results suggested, not only that NHE3 deficiency not only affected the colonic microbiota composition, but also that the intestinal microbiota modulates the severity of distal colitis in NHE3 Ϫ/Ϫ mice in a manner similar to broad-spectrum antibiotics (16).…”

Section: G671 Alteration Of the Gut Microbiome In Nhe3mentioning

confidence: 79%

Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

Larmonier

Laubitz

Hill

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: G671 Alteration Of the Gut Microbiome In Nhe3mentioning

confidence: 79%

Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

Larmonier

Laubitz

Hill

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Impaired electrolyte absorption is linked to a decrease in Na ϩ /H ϩ exchange activity in humans (33,36) and in animal models of inflammation (29,49). To explore whether NHE8 contributes to the impaired NHE function in the setting of inflammatory states, we studied the influence of inflammation on NHE8 expression in two animal models of inflammation, TNBS colitis and LPS endotoxinemia models.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor-α downregulates intestinal NHE8 expression by reducing basal promoter activity

Chen

Dong

et al. 2009

American Journal of Physiology-Cell Physiology

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transporter is a member of the sodium/hydrogen exchanger (NHE) family. This transporter protein is expressed at the apical membrane of epithelial cells of kidney and intestine and contributes to vectorial Na ϩ transport in both tissues. Although NaCl absorption has been shown to be reduced in diarrhea associated with colitis and enteritis, little is known about the role of Na ϩ /H ϩ exchange and the involvement of NHE isoforms in the pathogenesis of inflammatory disorders and the mechanism of inflammation-associated diarrhea. This study investigated the role of NHE8 in the setting of inflammatory states. Jejunal mucosa was harvested from trinitrobenzene sulfonic acid (TNBS) colitis rats or lipopolysaccharide (LPS) rats for RNA extraction and brush-border membrane protein purification. The human NHE8 gene promoter was cloned from human genomic DNA and characterized in Caco-2 cells. The promoter was further used to study the mechanisms of TNF-␣-mediated NHE8 expression downregulation in Caco-2 cells. Results from Western blot and real-time PCR indicated that NHE8 protein and mRNA were significantly reduced in TNBS rats and LPS rats. In Caco-2 cells, TNF-␣ produces similar reduction levels in the endogenous NHE8 mRNA expression observed in our in vivo studies. The downregulation of NHE8 expression mediated by TNF-␣ could be blocked by transcription inhibitor actinomycin D, suggesting the involvement of transcriptional regulation. Further studies indicated that the human NHE8 gene transcription could be activated by Sp3 transcriptional factor, and TNF-␣ inhibits human NHE8 expression by reducing Sp3 interaction at the minimal promoter region of the human NHE8 gene. In conclusion, our studies suggest that TNF-␣ decreases NHE8 expression in inflammation induced by TNBS and LPS, which may contribute to the diarrhea associated with inflammation. trinitrobenzene sulfonic acid colitis; sodium/hydrogen exchanger 8; intestine SODIUM/HYDROGEN EXCHANGERS (NHEs) are a group of integral transmembrane proteins that exchange extracellular Na ϩ for intracellular H ϩ . They are widely expressed in mammalian cells, with broad physiological functions from intracellular pH (pH i ) homeostasis and cell volume regulation to electroneutral NaCl transport. NHEs exhibit different tissue distribution, membrane localization, inhibitor sensitivity, and physiological regulation (2, 3, 6, 8 -11, 13-16, 18, 19, 21, 26, 30, 32, 34, 35, 37, 41, 50, 51). Additionally, these NHEs also play roles in several disorders such as diarrheal diseases, hypertension, and cardiac ischemia (53).To date, five NHEs have been found in the mammalian intestine. NHE1 protein is localized to the basolateral membrane in the intestinal epithelial cells (47, 48), and it contributes to cell volume regulation and pH i regulation (41). Absence of NHE1 in mice exhibits decreased postnatal growth rate, ataxia, and seizures (5). NHE2 protein is localized to the brush-border membrane (BBM) in the intestinal epithelia (22). NHE2-knockout mice display normal phenotype but have a...

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“…This criterion was selected after observing that the mean variance of all of the probes was 0.15, and the false positive rate was estimated to be 0.0032%. With similar multiple hybridizations and cDNA microarrays, the fold change of 1.3-1.4 was utilized to identify significant gene expression change in other studies (31)(32)(33). Additionally, significant fold changes required that the 95% CI of the fold change, two standard errors away from the fold change, excluded 1.…”

Section: Methodsmentioning

confidence: 99%

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

Ohsugi

Cras-Méneur

Zhou

et al. 2005

Journal of Biological Chemistry

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The role of insulin signaling in pancreatic ␤ cells has become increasingly apparent. Stably transformed insulinoma cell lines (MIN6) were created with small interfering RNA resulting in the reduction of insulin receptor (IR) expression up to 80% (insulin receptor knockdown, IRKD⌬80). Functionally perturbed IR signaling was confirmed with the absence of insulin-stimulated insulin receptor substrate 1 tyrosine phosphorylation. Additionally, Akt phosphorylation was reduced and responded poorly to glucose stimulation. Gene expression profiling revealed that reduced IR expression was associated with alterations in expression of >1,500 genes with diverse functions. IRKD cells exhibited low rate of proliferation due to delay in transition from G 0 /G 1 to S phase, whereas susceptibility to apoptosis did not differ from that of control cells. Insulin content was reduced in proportion to the reduction of IR. IRKD cells maintained glucose responsiveness as measured by NAD(P)H generation, whereas Ca 2؉ responses and insulin secretion were enhanced. IRKD⌬80 and control cells were treated with glucose (25 mM) or insulin (100 nM) for 45 min, and gene expression profiles were assessed. Transcriptional activation of several hundred early response genes common to both glucose and insulin stimulation was observed in control cells. In IRKD⌬80 cells, insulin failed to activate any genes as anticipated. Importantly, glucose stimulation of gene expression in IRKD⌬80 cells showed that most genes previously activated by glucose were no longer activated, suggesting a major autocrine/paracrine effect of insulin on glucoseregulated gene expression. On the other hand, there were a number of glucose-regulated genes in the IRKD⌬80 cells that were not previously observed in control cells, suggesting a feedback regulation of insulin signaling on glucose-regulated gene expression. These results demonstrate important roles of the insulin receptor in islet ␤ cell gene expression and function and may serve to elucidate molecular defects in animal models with diminished ␤ cell insulin signaling.Pancreatic ␤ cells dynamically adapt to their environment (1, 2). Changes in plasma glucose concentration along with various hormones and growth factors have been shown to be major determinants of insulin secretion, biosynthesis, and islet mass (3, 4). The islet ␤ cell responds to these changes in its environment by altering its transcriptional responses, and these changes in gene expression ultimately result in altered mass and function. However, the signaling pathways activated by these environmental changes and the ensuing transcriptional events that mediate these biological responses are only beginning to be elucidated. Specifically, the relationships between the signaling pathways activated by glucose and those activated by growth factors such as insulin remain unclear.The roles of insulin as a growth factor in the modulation of ␤ cell mass and function have been implied by the results of recent experiments. Glucose stimulation of ␤ cells in culture ha...

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In Vivo Evidence for Interferon-γ-mediated Homeostatic Mechanisms in Small Intestine of the NHE3 Na+/H+ Exchanger Knockout Model of Congenital Diarrhea

Cited by 43 publications

References 80 publications

Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

Tumor necrosis factor-α downregulates intestinal NHE8 expression by reducing basal promoter activity

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

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