Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis.
Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis.
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DOI：
10.1053/j.gastro.2009.12.002
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发表时间：
2010-04
期刊：
影响因子：
29.4
通讯作者：
Ghishan FK
中科院分区：
文献类型：
--
作者：
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
Klotho deficiency in hypomorphic KL mice leads to premature senescence and phenotype consistent with impaired mineral homeostasis. Klotho has anti-inflammatory properties protecting from NO-induced endothelial dysfunction, reduces the expression of endothelial adhesion molecules, and may contribute to T-cell dysfunction. Since defective Ca2+/Pi homeostasis leading to osteopenia/osteoporosis is frequently associated with human IBD, we investigated the changes in Klotho gene expression as a consequence of experimental colitis. We utilized three murine IBD models: TNBS colitis, microflora-induced colitis in gnotobiotic IL-10−/− mice, and adoptive CD4+CD45RBhigh T-cell transfer colitis. These studies were followed by in vitro approaches using renal epithelial cells (mpkDCT4 and mIMCD3), and the cloned murine KL gene promoter. Renal expression of Klotho mRNA and protein was significantly inhibited in all three models of human IBD. This degree of inhibition was correlated with the severity of colitis, and was reversed by neutralizing anti-TNF antibodies. In vitro, TNF resulted in a significant inhibition of KL expression and was further potentiated by IFN-γ. TNF/IFN-γ combination resulted in increased iNOS expression and significantly elevated the concentration of NO in medium. The effect of IFN-γ could be reproduced by cell exposure to SNAP (NO donor), and reversed by iNOS inhibitor, L-NIL. The cytokine effects were transcriptionally mediated since Klotho mRNA stability remained unaffected, while reporter constructs with the mKL gene promoter displayed significant downregulation in transiently transfected renal epithelial cells. These novel findings could help explain several extraintestinal complications including abnormalities in bone homeostasis in patients with chronic colitis.
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DOI：
10.1152/ajpgi.00433.2004
发表时间：
2005-04-01
影响因子：
4.5
作者：
Kiela, PR;Midura, AJ;Ghishan, FK
通讯作者：
Ghishan, FK
影响因子：
3.7
作者：
Joo YE;Karrasch T;Mühlbauer M;Allard B;Narula A;Herfarth HH;Jobin C
通讯作者：
Jobin C
DOI：
10.1006/bbrc.1998.9576
发表时间：
1998-10-29
影响因子：
3.1
作者：
Ohyama, Y;Kurabayashi, M;Nagail, R
通讯作者：
Nagail, R
影响因子：
--
作者：
RAUCHMAN, MI;NIGAM, SK;GULLANS, SR
通讯作者：
GULLANS, SR
影响因子：
19.6
作者：
Baum, M;Schiavi, S;Quigley, R
通讯作者：
Quigley, R