ABSTRACT
Mesenchymal stem cell (MSC)-based regenerative therapy is currently regarded as a novel approach with which to repair damaged tissues. However, the efficiency of MSC transplantation is limited due to the low survival rate of engrafted MSCs. Lipopolysaccharide (LPS) production is increased in numerous diseases and serves an essential function in the regulation of apoptosis in a variety of cell types. Previous studies have indicated that low-dose LPS pretreatment contributes to cytoprotection. In the current study, LPS was demonstrated to induce apoptosis in human umbilical cord mesenchymal stem cells (hUCMSCs) via the activation of caspase, in a dose-dependent manner. Low-dose LPS pretreatment may protect hUCMSCs against apoptosis induced by high-dose LPS, by upregulating the expression of cellular FADD-like IL-1ß-converting enzyme-inhibitory protein (c-FLIP). The results of the present study indicate that pretreatment with an appropriate concentration of LPS may alleviate high-dose LPS-induced apoptosis.
Subject(s)
CASP8 and FADD-Like Apoptosis Regulating Protein/immunology , Hormesis/immunology , Lipopolysaccharides/pharmacology , Mesenchymal Stem Cells/drug effects , Apoptosis/drug effects , CASP8 and FADD-Like Apoptosis Regulating Protein/agonists , CASP8 and FADD-Like Apoptosis Regulating Protein/antagonists & inhibitors , CASP8 and FADD-Like Apoptosis Regulating Protein/genetics , Caspase 3/genetics , Caspase 3/immunology , Caspase 8/genetics , Caspase 8/immunology , Cell Survival/drug effects , Cytoprotection , Fetal Blood/cytology , Fetal Blood/drug effects , Fetal Blood/immunology , Gene Expression Regulation , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/immunology , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/immunology , Signal TransductionABSTRACT
Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNFα-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIPL expression, the enhanced activation of NFκB and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects.
