Inhibition of ER stress-activated JNK pathway attenuates TNF-α-induced inflammatory response in bone marrow mesenchymal stem cells

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) are characterized by their pluripotent differentiation and self-renewal capability and have been widely applied in regenerative medicine, gene therapy, and tissue repair. However, inflammatory response after BMMSCs transplantation was found to impair the osteogenic differentiation of BMMSCs. Thus, understanding the mechanisms underlying inflammation response will benefit the clinical use of BMMSCs. In this study, using a cell model of TNF-α-induced inflammatory response, we found that TNF-α treatment greatly elevated intracellular oxidative stress and induced endoplasmic reticulum (ER) stress by elevating the expression levels of ER sensors, such as PERK, ATF6 and IRE1A. Oxidative stress and ER stress formed a feedback loop to mediate TNF-α-induced inflammation response in BMMSCs. Moreover, c-Jun N-terminal kinase (JNK) signal pathway that coupled to the ER stress was significantly activated by increasing its phosphorylation upon TNF-α treatment. Importantly, pharmacological inhibition of ER stress effectively eliminated the phosphorylation of JNK and attenuated the TNF-α-induced inflammation response. In conclusion, our results indicated that TNF-α induced oxidative and ER stress, thereby leading to JNK activation, and generating inflammation response in BMMSCs. This pathway underlying TNF-α-induced inflammation response may provide new strategies to improve BMMSCs osteogenesis and other inflammation-associated bone diseases.