The protective effects of lixisenatide against inflammatory response in human rheumatoid arthritis fibroblast-like synoviocytes

  • Int Immunopharmacol. 2019 Oct:75:105732. doi: 10.1016/j.intimp.2019.105732.
Xingye Du  1 ,  Hailin Zhang  2 ,  Wenhao Zhang  3 ,  Qing Wang  3 ,  Wei Wang  3 ,  Gaoren Ge  3 ,  Jiaxiang Bai  3 ,  Xiaobin Guo  3 ,  Yunqing Zhang  2 ,  Xuefeng Jiang  2 ,  Jiaye Gu  2 ,  Yaozeng Xu  4 ,  Dechun Geng  5
Affiliations
  • 1. Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Department of Orthopedics, Jiangyin Hospital Affiliated to Southeast University, Wuxi 214400, China.
  • 2. Department of Orthopedics, Jiangyin Hospital Affiliated to Southeast University, Wuxi 214400, China.
  • 3. Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
  • 4. Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China. Electronic address: [email protected].
  • 5. Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China. Electronic address: [email protected].
PMID: 31336333 DOI: 10.1016/j.intimp.2019.105732
Abstract

Rheumatoid arthritis (RA) is a major debilitating systemic disease characterized by chronic inflammation of the synovium and joint destruction. Despite major advancements in our understanding of RA in recent decades, it remains a disease of unknown etiology. To our knowledge, this is the first study exploring the effects of agonism of the glucagon-like peptide-1 (GLP-1) receptor using lixisenatide, a licensed drug used for the treatment of type II diabetes, on the pathological characteristics of RA in human fibroblast-like synoviocytes. Our findings indicate that lixisenatide inhibited the inflammatory response through downregulation of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); inhibition of Matrix Metalloproteinases (MMPs); and blockade of cellular signaling pathways, including the c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), and nuclear factor κ B (NF-κB) pathways. Furthermore, lixisenatide improved oxidative stress, rescued mitochondrial membrane potential (ΔΨm), and prevented cell death in fibroblast-like synoviocytes. These findings suggest that agonism of the GLP-1 Receptor using lixisenatide may serve as a novel therapeutic option for the treatment and prevention of RA.

Keywords
Fibroblast-like synoviocytes (FLSs); Inflammatory response; Interleukin 1β (IL-1β); Lixisenatide; Matrix metalloproteinases (MMPs); NF-κB signaling pathway; Rheumatoid arthritis (RA).
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