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(+)CD45RB(high) T cells. Effects of the tumor necrosis factor (TNF) and 
interferon (IFN)-gamma 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-gamma. The 
combination of TNF and IFN-gamma increased expression of inducible nitric oxide 
synthase (iNOS) and increased NO production. The effect of IFN-gamma was 
reproduced by exposure to an NO donor and reversed by the iNOS inhibitor. In 
cells incubated with TNF and/or IFN-gamma, 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.