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SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance.
Ann Rheum Dis. 2011 Oct; 70(10):1866-73.AR

Abstract

OBJECTIVE

To analyse the expression of SIRT1 in synovial tissues and cells of patients with rheumatoid arthritis (RA) and to study the function of SIRT1 in inflammation and apoptosis in RA.

METHODS

Levels of SIRT1 expression were analysed in synovial tissues and cells from patients with RA by real-time PCR and western blotting before and after stimulation with toll-like receptor ligands, tumour necrosis factor α (TNFα) and interleukin 1β (IL-1β). Immunohistochemistry was used to study the localisation of SIRT1. Fluorescence activated cell sorting analysis was performed to investigate the effect of SIRT1 on apoptosis. Peripheral blood monocytes and rheumatoid arthritis synovial fibroblasts (RASFs) were transfected with wild-type or enzymatically inactive SIRT1 expression vectors or with siRNA targeting SIRT1. Cytokine analysis of IL-6, IL-8 and TNFα were performed by ELISA to study the role of SIRT1 on proinflammatory mediators of RA.

RESULTS

SIRT1 was found to be constitutively upregulated in synovial tissues and cells from patients with RA compared to osteoarthritis. TNFα stimulation of RASFs and monocytes resulted in further induced expression levels of SIRT1. Silencing of SIRT1 promoted apoptosis in RASFs, whereas SIRT1 overexpression protected cells from apoptosis. Inhibition of SIRT1 enzymatic activity by inhibitors, siRNA and overexpression of an enzymatically inactive form of SIRT1 reduced lipopolysaccharide-induced levels of TNFα in monocytes. Similarly, knockdown of SIRT1 resulted in a reduction of proinflammatory IL-6 and IL-8 in RASFs.

CONCLUSION

The TNFα-induced overexpression of SIRT1 in RA synovial cells contributes to chronic inflammation by promoting proinflammatory cytokine production and inhibiting apoptosis.

Authors+Show Affiliations

Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21742641

Citation

Niederer, Fabienne, et al. "SIRT1 Overexpression in the Rheumatoid Arthritis Synovium Contributes to Proinflammatory Cytokine Production and Apoptosis Resistance." Annals of the Rheumatic Diseases, vol. 70, no. 10, 2011, pp. 1866-73.
Niederer F, Ospelt C, Brentano F, et al. SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. Ann Rheum Dis. 2011;70(10):1866-73.
Niederer, F., Ospelt, C., Brentano, F., Hottiger, M. O., Gay, R. E., Gay, S., Detmar, M., & Kyburz, D. (2011). SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. Annals of the Rheumatic Diseases, 70(10), 1866-73. https://doi.org/10.1136/ard.2010.148957
Niederer F, et al. SIRT1 Overexpression in the Rheumatoid Arthritis Synovium Contributes to Proinflammatory Cytokine Production and Apoptosis Resistance. Ann Rheum Dis. 2011;70(10):1866-73. PubMed PMID: 21742641.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. AU - Niederer,Fabienne, AU - Ospelt,Caroline, AU - Brentano,Fabia, AU - Hottiger,Michael O, AU - Gay,Renate E, AU - Gay,Steffen, AU - Detmar,Michael, AU - Kyburz,Diego, Y1 - 2011/07/08/ PY - 2011/7/12/entrez PY - 2011/7/12/pubmed PY - 2011/11/10/medline SP - 1866 EP - 73 JF - Annals of the rheumatic diseases JO - Ann. Rheum. Dis. VL - 70 IS - 10 N2 - OBJECTIVE: To analyse the expression of SIRT1 in synovial tissues and cells of patients with rheumatoid arthritis (RA) and to study the function of SIRT1 in inflammation and apoptosis in RA. METHODS: Levels of SIRT1 expression were analysed in synovial tissues and cells from patients with RA by real-time PCR and western blotting before and after stimulation with toll-like receptor ligands, tumour necrosis factor α (TNFα) and interleukin 1β (IL-1β). Immunohistochemistry was used to study the localisation of SIRT1. Fluorescence activated cell sorting analysis was performed to investigate the effect of SIRT1 on apoptosis. Peripheral blood monocytes and rheumatoid arthritis synovial fibroblasts (RASFs) were transfected with wild-type or enzymatically inactive SIRT1 expression vectors or with siRNA targeting SIRT1. Cytokine analysis of IL-6, IL-8 and TNFα were performed by ELISA to study the role of SIRT1 on proinflammatory mediators of RA. RESULTS: SIRT1 was found to be constitutively upregulated in synovial tissues and cells from patients with RA compared to osteoarthritis. TNFα stimulation of RASFs and monocytes resulted in further induced expression levels of SIRT1. Silencing of SIRT1 promoted apoptosis in RASFs, whereas SIRT1 overexpression protected cells from apoptosis. Inhibition of SIRT1 enzymatic activity by inhibitors, siRNA and overexpression of an enzymatically inactive form of SIRT1 reduced lipopolysaccharide-induced levels of TNFα in monocytes. Similarly, knockdown of SIRT1 resulted in a reduction of proinflammatory IL-6 and IL-8 in RASFs. CONCLUSION: The TNFα-induced overexpression of SIRT1 in RA synovial cells contributes to chronic inflammation by promoting proinflammatory cytokine production and inhibiting apoptosis. SN - 1468-2060 UR - https://www.unboundmedicine.com/medline/citation/21742641/SIRT1_overexpression_in_the_rheumatoid_arthritis_synovium_contributes_to_proinflammatory_cytokine_production_and_apoptosis_resistance_ L2 - https://ard.bmj.com/cgi/pmidlookup?view=long&pmid=21742641 DB - PRIME DP - Unbound Medicine ER -