Transforming growth factor-β1-regulated Fas/FasL pathway activation suppresses nucleus pulposus cell apoptosis in an inflammatory environment

Abstract

Background: During disc degeneration, inflammatory cytokine tumor necrosis factor (TNF)-α is correlated with nucleus pulposus (NP) cell apoptosis. Transforming growth factor (TGF)-β1 has the potential to regenerate degenerative disc. Objective: To investigate the protective role of TGF-β1 against TNF-α-mediated NP cell apoptosis and the underlying mechanism. Methods: Rat NP cells were treated with TNF-α (100 ng/ml) for 48 h. TGF-β1 was added into the culture medium to investigate its protective effects against TNF-α-induced NP cell apoptosis. Exogenous FasL was used to investigate the potential role of the Fas/FasL pathway in this process. Flow cytometry assay was used to analyze NP cell apoptosis. Real-time PCR and Western blotting were used to analyze gene and protein expression of apoptosis-related molecules. Results: In TNF-α-treated NP cells, TGF-β1 significantly decreased NP cell apoptosis, declined caspase-3 and -8 activity, and decreased expression of Bax and caspase-3 (cleaved-caspase-3) but increased expression of Bcl-2. However, exogenous FasL partly reversed these effects of TGF-β1 in NP cells treated with TNF-α. Additionally, expression of Fas and FasL in TNF-α-treated NP cells partly decreased by TGF-β1, whereas exogenous FasL increased expression of Fas and FasL in NP cells treated with TGF-β1 and TNF-α. Conclusion: TGF-β1 helps to inhibit TNF-α-induced NP cell apoptosis and the Fas/FasL pathway may be involved in this process. The present study suggests that TGF-β1 may be effective to retard inflammation-mediated disc degeneration.

Lumican silencing alleviates tumor necrosis factor-α-induced nucleus pulposus cell inflammation and senescence by inhibiting apoptosis signal regulating kinase 1/p38 signaling pathway via inactivating Fas ligand expression

“…It has been reported that LUM can be co-immunoprecipitated with FasL to induce fibroblast apoptosis and inflammatory response [ 24 ]. Noteworthy, exogenous FasL could diminish the protective effect of TGF-β1 on TNF-α-challenged hNPCs [ 25 ]. Additionally, the bioinformatics analysis employing KEGG database ( https://www.kegg.jp/ ) found that FasL might regulate the expression of downstream ASK1 and p38 together identified as a key pathway of cell apoptosis and senescence [ 26 ].…”

“…Earlier studies have demonstrated that increased proliferation and decreased apoptosis of corneal fibroblasts in LUM-absent mice, and that LUM could be co-immunoprecipitated with FasL to induce fibroblast apoptosis and inflammatory response [ 24 , 35 ]. Noteworthy, exogenous FasL could diminish the protective effect of TGF-β1 on TNF-α-challenged hNPCs [ 25 ]. Our results showed that the level of FasL was much higher in the TNF-α group than in the control group, whereas interference with LUM brought down the level of FasL in TNF-α-challenged hNPCs.…”

“…It has been reported that LUM can be coimmunoprecipitated with FasL to induce fibroblast apoptosis and inflammatory response [24]. Noteworthy, exogenous FasL could diminish the protective effect of TGF-β1 on TNF-α-challenged hNPCs [25]. Additionally, the bioinformatics analysis employing KEGG database (https://www.…”

Targeted therapy for intervertebral disc degeneration: inhibiting apoptosis is a promising treatment strategy

“…Transforming growth factor-β1 (TGF-β1) has the potential to regenerate the IVD. Xie et al 86 showed that TGF-β1 significantly reduced apoptosis in rat NPCs treated with TNF-α and decreased the activities of caspase-3 and caspase-8.…”

The Golgi Apparatus May Be a Potential Therapeutic Target for Apoptosis-Related Neurological Diseases

“…Fas (also known as CD95) is a member of the TNFR superfamily, which transmits apoptotic signals by binding to Fas ligand (FasL) expressed in the cell membranes of other cells (Andera, 2009;Xie et al, 2019). The Fas-FasL system is a major signaling pathway for apoptosis induction.…”