Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

• Автори: Chen D (Автор), Cai X (Автор), Ouyang H (Автор), Yuan S (Автор), Wang X (Автор), Lin L (Автор), chen Z (Автор), Huang M (Автор)
• Формат: Книга
• Опубліковано: Dove Medical Press, 2022-03-01T00:00:00Z.
• Предмети: article
• Онлайн доступ: Connect to this object online.
• Notes: 1178-7031
• Keywords: rheumatoid arthritis; fibroblast-like synoviocytes; eukaryotic elongation factor-2 kinase; glycolysis; migration; invasion; Pathology; RB1-214; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Inflammation Research, Vol Volume 15, Pp 1729-1744 (2022)

Dongying Chen,1,* Xiaoyan Cai,2,* Hui Ouyang,3,* Shiwen Yuan,2 Xiaodong Wang,4 Lian Lin,5 Zhiqing Chen,5 Mingcheng Huang5 1Department of Rheumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guandong, People's Republic of China; 2Department of Rheumatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guandong, People's Republic of China; 3Department of Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, ShenZhen, Guandong, People's Republic of China; 4Department of Ultrasound, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guandong, People's Republic of China; 5Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, ShenZhen, Guandong, People's Republic of China*These authors contributed equally to this workCorrespondence: Mingcheng Huang, Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, ShenZhen, Guandong, People's Republic of China, Email [e-mail]: Aggressive phenotype and abnormal glycolytic metabolism of fibroblast-like synoviocytes (FLSs) are essential to joint inflammation and damage in rheumatoid arthritis (RA). Eukaryotic elongation factor-2 kinase (eEF2K) is a negative regulator of protein synthesis and has been shown to play an important role in regulating various cellular processes and promoting glycolysis in tumor cells. However, the role of eEF2K in regulating the pathogenic FLS behaviors is unknown.Methods: A specific inhibitor of eEF2K, NH125, and siRNA were used to evaluate the role of eEF2K on RA FLSs in vitro. Collagen-induced arthritis (CIA) mice were used to evaluate the in vivo effect of eEF2K. Cell migration, invasion of RA FLSs were assessed by transwell or wound healing assays. Relative changes of cytokines were analyzed by quantitative real-time PCR, western blot and ELISA.Results: Herein, we found an increased expression of eEF2K in synovial tissues and FLSs of RA patients. eEF2K knockdown by siRNA or treatment with NH125, an inhibitor of eEF2K, significantly reduced inflammation, migration/invasion, glucose uptake and lactate productions. eEF2K knockdown suppressed TNF-α-induced activation of NF-κB and AKT pathways in RA FLSs. Lactate reversed the inhibitory effect of eEF2K knockdown on inflammation and migration of RA FLSs. Moreover, lactate was also involved in eEF2K-mediated activation of NF-κB and AKT. NH125 treatment attenuated the severity of arthritis in collagen-induced arthritis mice.Conclusion: eEF2K inhibition suppressed glycolysis and aggressive behaviors of RA FLS, which indicated that targeting eEF2K may be a new strategy for the treatment of RA.Keywords: rheumatoid arthritis, fibroblast-like synoviocytes, eukaryotic elongation factor-2 kinase, glycolysis, migration, invasion