Tumor Necrosis Factor and Interferon-γ Down-regulate Klotho in Mice With Colitis

Robert D. Thurston, Claire B. Larmonier, Pawel M. Majewski, Rajalakshmy Ramalingam, Monica Midura-Kiela, Daniel Laubitz, Alain Vandewalle, David G. Besselsen, Marcus Mühlbauer, Christian Jobin, Pawel R. Kiela, Fayez K. Ghishan

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83 Scopus citations

Abstract

Background & Aims: Klotho (KL) is an anti-inflammatory protein that protects the endothelium from nitric oxide (NO)-induced dysfunction, reduces the expression of endothelial adhesion molecules, and potentially regulates T-cell functions. KL deficiency leads to premature senescence and impaired Ca2+/Pi homeostasis, which can lead to inflammatory bowel disease (IBD)-associated osteopenia/osteoporosis. We investigated the changes in renal expression of Kl as a consequence of colitis. Methods: We studied 3 mouse models of IBD: colitis induced by trinitrobenzene sulfonic acid, colitis induced by microflora (in gnotobiotic interleukin-10-/-), and colitis induced by adoptive transfer of CD4+CD45RBhigh T cells. Effects of the tumor necrosis factor (TNF) and interferon (IFN)-γ on Kl expression and the activity of its promoter were examined in renal epithelial cells (mpkDCT4 and mIMCD3). Results: Renal expression of Kl messenger RNA (mRNA) and protein was reduced in all 3 models of IBD. Reduced level of KL correlated with the severity of colitis; the effect was reversed by neutralizing antibodies against TNF. In vitro, TNF inhibited Kl expression, an effect potentiated by IFN-γ. The combination of TNF and IFN-γ increased expression of inducible nitric oxide synthase (iNOS) and increased NO production. The effect of IFN-γ was reproduced by exposure to an NO donor and reversed by the iNOS inhibitor. In cells incubated with TNF and/or IFN-γ, Kl mRNA stability was unaffected, whereas Kl promoter activity was reduced, indicating that these cytokines regulate Kl at the transcriptional level. Conclusions: The down-regulation of KL that occurs during inflammation might account for the extraintestinal complications such as abnormalities in bone homeostasis that occur in patients with IBD.

Original languageEnglish (US)
Pages (from-to)1384-1394.e2
JournalGastroenterology
Volume138
Issue number4
DOIs
StatePublished - Apr 2010

Keywords

  • Bone Metabolism
  • Distal Convoluted Tubules
  • Kidney
  • Mineral Homeostasis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Thurston, R. D., Larmonier, C. B., Majewski, P. M., Ramalingam, R., Midura-Kiela, M., Laubitz, D., Vandewalle, A., Besselsen, D. G., Mühlbauer, M., Jobin, C., Kiela, P. R., & Ghishan, F. K. (2010). Tumor Necrosis Factor and Interferon-γ Down-regulate Klotho in Mice With Colitis. Gastroenterology, 138(4), 1384-1394.e2. https://doi.org/10.1053/j.gastro.2009.12.002