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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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)
JournalGastroenterology
Volume138
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

Colitis
Interferons
Down-Regulation
Tumor Necrosis Factor-alpha
Inflammatory Bowel Diseases
Nitric Oxide Synthase Type II
Kidney
Nitric Oxide
Homeostasis
Trinitrobenzenes
Germ-Free Life
T-Lymphocytes
Messenger RNA
Sulfonic Acids
Nitric Oxide Donors
Adoptive Transfer
Metabolic Bone Diseases
RNA Stability
Neutralizing Antibodies
Interleukin-10

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tumor Necrosis Factor and Interferon-γ Down-regulate Klotho in Mice With Colitis. / Thurston, Robert D.; Larmonier, Claire B; Majewski, Pawel M.; Ramalingam, Rajalakshmy; Midura-Kiela, Monica; Laubitz, Daniel; Vandewalle, Alain; Besselsen, David G.; Mühlbauer, Marcus; Jobin, Christian; Kiela, Pawel R; Ghishan, Fayez K.

In: Gastroenterology, Vol. 138, No. 4, 04.2010.

Research output: Contribution to journalArticle

Thurston, RD, Larmonier, CB, Majewski, PM, Ramalingam, R, Midura-Kiela, M, Laubitz, D, Vandewalle, A, Besselsen, DG, Mühlbauer, M, Jobin, C, Kiela, PR & Ghishan, FK 2010, 'Tumor Necrosis Factor and Interferon-γ Down-regulate Klotho in Mice With Colitis', Gastroenterology, vol. 138, no. 4. https://doi.org/10.1053/j.gastro.2009.12.002
Thurston, Robert D. ; Larmonier, Claire B ; Majewski, Pawel M. ; Ramalingam, Rajalakshmy ; Midura-Kiela, Monica ; Laubitz, Daniel ; Vandewalle, Alain ; Besselsen, David G. ; Mühlbauer, Marcus ; Jobin, Christian ; Kiela, Pawel R ; Ghishan, Fayez K. / Tumor Necrosis Factor and Interferon-γ Down-regulate Klotho in Mice With Colitis. In: Gastroenterology. 2010 ; Vol. 138, No. 4.
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AU - Thurston, Robert D.

AU - Larmonier, Claire B

AU - Majewski, Pawel M.

AU - Ramalingam, Rajalakshmy

AU - Midura-Kiela, Monica

AU - Laubitz, Daniel

AU - Vandewalle, Alain

AU - Besselsen, David G.

AU - Mühlbauer, Marcus

AU - Jobin, Christian

AU - Kiela, Pawel R

AU - Ghishan, Fayez K

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N2 - 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.

AB - 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.

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