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

摘要: Background & Aims Klotho (KL) is an anti-inflammatory protein that protects the endothelium from nitric oxide (NO)-induced dysfunction, reduces expression of endothelial adhesion molecules, and potentially regulates T-cell functions. KL deficiency leads to premature senescence impaired Ca2+/Pi homeostasis, which can lead inflammatory bowel disease (IBD)-associated osteopenia/osteoporosis. We investigated changes in renal Kl as a consequence colitis. Methods studied 3 mouse models IBD: colitis induced by trinitrobenzene sulfonic acid, microflora (in gnotobiotic interleukin- 10 −/− ), adoptive transfer CD4 + CD45RB high T cells. Effects tumor necrosis factor (TNF) interferon (IFN)-γ on activity its promoter were examined epithelial cells (mpkDCT4 mIMCD3). Results Renal messenger RNA (mRNA) was reduced all IBD. Reduced level correlated with severity colitis; effect reversed neutralizing antibodies against TNF. In vitro, TNF inhibited expression, potentiated IFN-γ. The combination IFN-γ increased inducible synthase (iNOS) NO production. reproduced exposure donor iNOS inhibitor. incubated and/or IFN-γ, mRNA stability unaffected, whereas reduced, indicating these cytokines regulate at transcriptional level. Conclusions down-regulation occurs during inflammation might account for extraintestinal complications such abnormalities bone homeostasis occur patients