SIRT1 Inhibits the Catabolic Effect of IL-1β Through TLR2/SIRT1/NF-κB Pathway in Human Degenerative Nucleus Pulposus Cells

Abstract

Background: Low back pain (LBP), one of the most prominent problems worldwide, lacks effective disease-modifying medical therapy. Intervertebral disc degeneration (IVDD) is a major cause of LBP, and proinflammatory cytokines are the key factors involved in the development of IVDD-induced back pain. Sirtuin 1 (SIRT1) is implicated in the molecular control of aging and immune responses in various diseases; however, its effect on IVDD is not clearly understood. Objective: To investigate the effects of SIRT1 on proinflammatory stress and signal transduction pathways induced by interleukin-1β (IL-1β) in human degenerative nucleus pulposus (NP) cells. Study Design: Research study. Setting: Chongqing Key Laboratory of Ophthalmology. Methods: Anti-apoptotic and anti-catabolic effects of SIRT1 on IL-1β were investigated using a three-dimensional cell culture model of prestimulated human NP cells transfected with a lentiviral vector overexpressing SIRT1 or a small-interfering RNA (siRNA) against the gene encoding SIRT1. In addition, molecular mechanisms underlying the association of SIRT1 with Toll-like receptor-2 (TLR2) and nuclear factor kappa B (NF-κB) were investigated. Results: Our results indicated that decreased SIRT1 expression was associated with IVDD. Direct regulation of SIRT1 expression did not affect the synthesis of extracellular matrix (ECM). However, SIRT1 overexpression mediated by the lentiviral vector suppressed IL-1β-induced ECM degradation and cell apoptosis. In contrast, knockdown of the gene encoding SIRT1 by the siRNA increased MMP expression and cell apoptosis induced by IL-1β. Furthermore, SIRT1 deacetylated RelA/p65 to inhibit the nuclear translocation of NF-κB, thus inhibiting inflammation. On the other hand, IL-1β downregulated SIRT1 expression by activating TLR2. However, inhibition of TLR2 expression by an siRNA did not inhibit IL-1β-induced nuclear translocation of NF-κB. Limitations: Limitations of this study were the in vitro study design and lack of in vivo validation of the observed effects of SIRT1 on IVDD. Conclusions: Our results indicated that SIRT1 exerted anti-inflammatory effects against IL-1βmediated degeneration of NP cells through the TLR2/SIRT1/NF-κB pathway, suggesting that it could be used as a potential candidate for treating IVDD-mediated back pain. Key words: SIRT1, TLR2, NF-κB, intervertebral disc degeneration