Open AccessSIRT1 Inhibits the Catabolic Effect of IL-1β Through TLR2/SIRT1/NF-κB Pathway in Human Degenerative Nucleus Pulposus Cells
Author(s) -
Zhenming Hu
Publication year - 2016
Publication title -
pain physician
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.31
H-Index - 99
eISSN - 2150-1149
pISSN - 1533-3159
DOI - 10.36076/ppj/2016.19.e215
Subject(s) - proinflammatory cytokine , gene knockdown , microbiology and biotechnology , tlr2 , medicine , small interfering rna , transfection , cancer research , signal transduction , sirtuin 1 , apoptosis , inflammation , biology , cell culture , downregulation and upregulation , immunology , tlr4 , gene , biochemistry , genetics
Background: Low back pain (LBP), one of the most prominent problems worldwide, lackseffective disease-modifying medical therapy. Intervertebral disc degeneration (IVDD) is a majorcause of LBP, and proinflammatory cytokines are the key factors involved in the developmentof IVDD-induced back pain. Sirtuin 1 (SIRT1) is implicated in the molecular control of aging andimmune 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 transductionpathways 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 usinga three-dimensional cell culture model of prestimulated human NP cells transfected with alentiviral vector overexpressing SIRT1 or a small-interfering RNA (siRNA) against the geneencoding SIRT1. In addition, molecular mechanisms underlying the association of SIRT1 withToll-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-inducedECM degradation and cell apoptosis. In contrast, knockdown of the gene encoding SIRT1by 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 inhibitinginflammation. 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 nucleartranslocation of NF-κB.Limitations: Limitations of this study were the in vitro study design and lack of in vivovalidation 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 itcould be used as a potential candidate for treating IVDD-mediated back pain.Key words: SIRT1, TLR2, NF-κB, intervertebral disc degeneration