Sprouty2 suppresses the inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes through regulating the Raf/ERK and PTEN/AKT signals.
AKT and ERK pathways are known to be activated in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), which play crucial roles in the pathogenesis and joint destruction of RA. Sprouty2 (SPRY2) has been known as a tumor suppressor by preventing both ERK and AKT signaling activations. Whether SPRY2 can function as a suppressor in tumor-like inflammatory FLS through negatively regulating AKT and ERK pathways, has not been reported. The purpose of this study was to determine whether SPRY2 might have antiinflammatory effects on RA FLS. The recombinant adenovirus containing SPRY2 complementary DNA (AdSPRY2) was used to deliver SPRY2 and express the protein in RA FLS. Adenoviral vector encoding green fluorescent protein (AdGFP) was used as the control. AdSPRY2 treatment suppressed the production of proinflammatory cytokines and matrix metalloproteinases (MMPs), and the cell proliferation, induced by TNFα in RA FLS. SPRY2 overexpression reduced AKT and ERK phosphorylation in TNFα-stimulated FLS, through mediating or interfering with the activity of PTEN or Raf respectively. These results suggest that using SPRY2 to block the AKT and ERK pathways suppresses the inflammatory responses of RA FLS, and the development of an immunoregulatory strategy based on SPRY2 may therefore have therapeutic potential in the treatment of RA.
Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing 100850, China. Electronic address: zhangweiyh@126.com.
Wei
W
Zhang
Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing 100850, China.
Zhiyan
Z
Du
Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing 100850, China.
Jingying
J
Zhu
Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing 100850, China.
Jiyun
J
Yu
Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing 100850, China.
Yuanji
Y
Xu
D000256:Adenoviridae / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013583:Synovial Membrane / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048490:raf Kinases / Q000378:metabolism*
D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485561:SPRY2 protein, human; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D051059:PTEN Phosphohydrolase
Fibroblast-like synoviocytes; Inflammatory responses; Rheumatoid arthritis; Signaling pathways; Sprouty2