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Inflammatory cytokines induce caveolin-1/?-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway.

ABSTRACT: OBJECTIVES:Apoptosis of nucleus pulposus (NP) cells is a major cause of intervertebral disc degeneration. To elucidate relationships between caveolin-1 and cytokine-induced apoptosis, we investigated the role of caveolin-1 in cytokine-induced apoptosis in rat NP cells and the related signalling pathway. MATERIALS AND METHODS:Rat NP cells were treated with interleukin (IL)-1? or tumour necrosis factor alpha (TNF-?), and knockdown of caveolin-1 and ?-catenin was achieved using specific siRNAs. Then, apoptotic level of rat NP cells and expression and activation of caveolin-1/?-catenin signalling were assessed by flow cytometric analysis, qRT-PCR, western blotting and luciferase assays. The relationship between the mitogen-activated protein kinase (MAPK) pathway and caveolin-1 promoter activity was also determined by luciferase assays. RESULTS:IL-1? and TNF-? induced apoptosis, upregulated caveolin-1 expression and activated Wnt/?-catenin signalling in rat NP cells, while the induction effect of cytokines was reversed by caveolin-1 siRNA and ?-catenin siRNA. Promotion of rat NP cell apoptosis and nuclear translocation of ?-catenin induced by caveolin-1 overexpression were abolished by ?-catenin siRNA. Furthermore, pretreatment with a p38 MAPK inhibitor or dominant negative-p38, blocked cytokine-dependent induction of caveolin-1/?-catenin expression and activity. CONCLUSIONS:The results revealed the role of p38/caveolin-1/?-catenin in inflammatory cytokine-induced apoptosis in rat NP cells. Thus, controlling p38/caveolin-1/?-catenin activity seemed to regulate IL-1?- and TNF-?-induced apoptosis in the NP during intervertebral disc degeneration.

SUBMITTER: Wang J

PROVIDER: S-EPMC6496863 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Inflammatory cytokines induce caveolin-1/β-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway.

Wang Jianxi J Chen Huajiang H Cao Peng P Wu Xiaodong X Zang Fazhi F Shi Liangyu L Liang Lei L Yuan Wen W

Cell proliferation 20160429 3

<h4>Objectives</h4>Apoptosis of nucleus pulposus (NP) cells is a major cause of intervertebral disc degeneration. To elucidate relationships between caveolin-1 and cytokine-induced apoptosis, we investigated the role of caveolin-1 in cytokine-induced apoptosis in rat NP cells and the related signalling pathway.<h4>Materials and methods</h4>Rat NP cells were treated with interleukin (IL)-1β or tumour necrosis factor alpha (TNF-α), and knockdown of caveolin-1 and β-catenin was achieved using speci ...[more]

PMID: 27125453

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Project description:BackgroundThe mechanisms underlying M2 macrophage polarization induced by nucleus pulposus (NP) cells are unclear. The effects that M2-polarized macrophages have on NP cells are also controversial.MethodsTranscriptome sequencing was performed to detect the gene change profiles between NP cells from ruptured intervertebral disc (IVD) and normal IVD. The main difference on biological activities between the two cell groups were analyzed by GO analysis and KEGG analysis. Virus transduction, flow cytometry, immunofluorescence, RT-PCR, western blot, CCK-8, TUNEL staining, and AO/EB staining were performed to explore the interactions between NP cells and RAW264.7 macrophages. Statistics were performed using SPSS26.Results801 upregulated and 276 downregulated genes were identified in NP cells from ruptured IVD in mouse models. According to GO and KEGG analysis, we found that the differentially expressed genes (DEG) were dominantly enriched in inflammatory response, extracellular matrix degradation, blood vessel morphogenesis, immune effector process, ossification, chemokine signaling pathway, macrophage activation, etc. CX3CL1 was one of the top 20% DEG, and we confirmed that both NP tissue and cells expressed remarkably higher level of CX3CL1 in mouse models (p < 0.001∗). Besides, we further revealed that both the recombinant CX3CL1 and NP cells remarkably induced M2 polarization of RAW264.7 (p < 0.001∗), respectively, while this effect was significantly reversed by si-CX3CL1 or JMS-17-2 (p < 0.001∗). Furthermore, we found that M2 macrophages significantly decreased the apoptosis rate (p < 0.001∗) and the catabolic gene levels (p < 0.001∗) of NP cells, while increased the viability, proliferation as well as the anabolic gene levels of NP cells (p < 0.01∗).ConclusionsVia regulating CX3CL1/CX3CR1 pathway, NP cells can induce the M2 macrophage polarization. M2 polarized macrophages can further promote NP cell viability, proliferation, and anabolism, while inhibit NP cell apoptosis and catabolism.

Dataset Information

Inflammatory cytokines induce caveolin-1/?-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway.

Publications

Inflammatory cytokines induce caveolin-1/β-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway.

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