Regulation Of Tumor Necrosis Factor-Alpha By Peptide Lv In Bone Marrow Macrophages And Synovium
FRONTIERS IN MEDICINE(2021)
Abstract
Background: Bone marrow-derived monocytes/macrophages are recruited into synovial tissue, where they contribute to synovial inflammation in osteoarthritis through inflammatory cytokine production. Recent studies have suggested that V-Set and transmembrane domain-containing 4 (VSTM4) and its fragment, peptide Lv, exhibit immunosuppressive activity on T cells and vascular endothelial growth factor (VEGF)-like activity, respectively. Given that evidence suggests that VEGF may play a role in macrophage function, we investigated peptide Lv-mediated regulation of inflammatory cytokines in bone marrow macrophages (BMMs) and synovial inflammation.Method: To investigate the effects of peptide Lv, BMMs were stimulated with vehicle, LPS, or LPS + peptide Lv, and Tnfa, Il1b, Il6, and Ifng expression were evaluated using quantitative PCR (qPCR). TNF-alpha and IFN-gamma production was measured using ELISA. To examine the effect of peptide Lv deficiency on macrophages and synovitis, peptide Lv-deficient mice were generated using genome editing. LPS-induced Tnfa and Ifng expression and TNF-alpha and IFN-gamma production were evaluated in BMM isolated from wild-type and peptide Lv-deficient mice. Additionally, Tnfa and Ifng expression levels were compared between wild-type and peptide Lv-deficient mice before and after knee injury.Results: Peptide Lv suppressed the LPS-mediated elevation in TNF-alpha and IFN-gamma. LPS stimulation significantly increased TNF-alpha and IFN-gamma production in BMM derived from peptide Lv-deficient mice compared to wild-type mice. Synovial TNF-alpha expression in the injured knee was elevated in peptide Lv-deficient compared to wild-type mice.Conclusion: Peptide Lv suppressed TNF-alpha in macrophages and plays a role in synovial inflammation. Thus, peptide Lv may be a useful therapeutic target for synovitis.
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Key words
V-set and transmembrane domain-containing 4, peptide Lv, tumor necrosis factor-alpha, macrophage, synovitis
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