Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7.
TGF-beta has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-beta in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-beta1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-beta1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1beta, TNF-alpha, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-beta1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-beta1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IkappaBalpha and a suppression of NF-kappaB activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-beta-NF-kappaB cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IkappaBalpha directly in a time- and dose-dependent manner, thereby inhibiting NF-kappaB activation and NF-kappaB-driven inflammatory response. In conclusion, latent TGF-beta may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-kappaB activation via the induction of IkBalpha may be the central mechanism by which latent TGF-beta prevents renal inflammation.
Wang
Wansheng
W
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Alkek N520, Houston, Texas 77030, USA.
Huang
Xiao R
XR
Li
Allen G
AG
Liu
Fang
F
Li
Jin-Hua
JH
Truong
Luan D
LD
Wang
Xiao J
XJ
Lan
Hui Y
HY
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000502:physiology; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000097:blood* / Q000235:genetics / Q000276:immunology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1