Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: Scleroderma is an autoimmune disease, characterized by progressive fibrosis of skin and internal organs. Inflammation is one of the main manifestations of scleroderma, especially at the early stage. Inflammation is also an important initiating agent of fibrosis, suppression of inflammation may be a promising resolution to attenuate scleroderma. Sirt1 (a NAD+dependent deacetylase) and its potent activator, resveratrol, both have been shown to have important role in regulation of inflammation.
Methods: In this study, we investigated the anti-inflammation role of Sirt1 and resveratrol in TNF-α treated fibroblasts and bleomycin induced mice experimental scleroderma, and further explore the anti-inflammatory mechanisms of Sirt1 and resveratrol in fibroblasts.
Results: Upregulation of matrix metalloproteinases 9 (MMP9), interleukin-1beta (IL-1β), IL-6 and inducible nitric oxide synthase (iNOS) were observed in the 3T3/NIH fibroblasts after being treated by TNF-α. Resveratrol suppressed the upregulation of inflammatory factors induced by TNF-α in a dose-dependent manner. And the suppression was significantly decreased if resveratrol was applied after the inflammation being induced. In the scleroderma mice model, bleomycin induced significant inflammation and fibrosis in the skin where infiltrated inflammatory cells, increased fiber bundles, upregulated collagen deposition were examined by HE staining and Masson’s trichrome staining. But the pathological changes in were then notably attenuated by resveratrol treatment in time and dose dependent manner. The bleomycin induced upregulation of inflammatory factors were also inhibited by resveratrol treatment in the mice skin. We further explored the potential anti-inflammatory mechanisms of resveratrol in vitro. We blocked Sirt1 expression by Sirt1 siRNA transfection in 3T3/NIH fibroblasts, and investigated that knockdown of Sirt1 caused cell sensitizing to TNF-α stimulation and diminished the inflammatory inhibition of resveratrol. Furthermore, in this study, we also found that resveratrol inhibited the phosphorylation of both mammalian target of rapamycin (mTOR) and S6 ribosomal protein (S6RP) while ameliorating the inflammation in TNF-α treated fibroblasts. And rapamycin, the specific inhibitor of mTOR, attenuated the TNF-α induced inflammation in the fibroblasts.
Conclusion: The results suggest that Sirt1 is an efficient target for suppression of inflammation and fibrosis in scleroderma. As a Sirt1 activator, resveratrol may be used for therapy in scleroderma. Suppression of mTOR/S6RP phosphorylation may be involved in the mechanisms. This study provides a novel insight or treatment of scleroderma and other inflammation-related diseases.
Disclosure:
X. Zhu,
None;
J. Qiu,
None;
Q. Liu,
None;
M. Liang,
None;
H. Zou,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-sirt1-attenuates-bleomycin-induced-scleroderma-through-inhibiting-mammalian-target-of-rapamycin-activation/