Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis

Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of inflammation.Jumonji domain-containing protein 3(JMJD3)is implicated in the immune response and inflammation.Here,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic mice.Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression.In addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone erosion.Conversely,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs.Furthermore,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes.GSK-J4 markedly attenuated the severity of arthritis in CIA mice.In conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

Anti-inflammatory effects of aucubin in cellular and animal models of rheumatoid arthritis

Rheumatoid arthritis(RA)is a chronic inflammatory autoimmune disease.It is known that aucubin(AU)exerts anti-inflammatory activity,but its effects and mechanisms in RA are unclear.This study investigated the anti-inflammatory effects and mechanisms of AU in vivo and in vitro.Human fibroblast-like synoviocyte cells from patients with RA(HFLS-RA),RAW264.7 cells,and MC3T3-E1 cells were used to evaluate the effects of AU on migration,invasion,apoptosis,osteoclast differentiation and production.Immunofluorescence was used to observe nuclear translocation of nuclear factor(NF)-/cB,the double luciferase reporter gene method was used to observe NF-/cB-p65 activity in AU-treated MC3T3-E1 cells.RT-qPCR was used to measure expression of bone metabolism and inflammation-related genes,and western blot was used to measure bone metabolism and NF-a:B protein expression levels.Collagen-induced arthritis(CIA)rat model was used for pharmacodynamics study.Arthritis indexes were measured in the ankle and knee,histological staining and Micro-computed tomography were performed on the ankle joints.Also,inflammatory factor gene expression and the levels of NF-/cB-related proteins were detected as in vitro.AU effectively inhibited HFLS-RA cell migration and invasion,promoted apoptosis,and inhibited RAW264.7 cell differentiation into osteoclasts,as well as inhibited NF-/cB-p65 activity in MC3T3-E1 cells.Notably,AU significantly reduced the gene expression levels of three cell-related inflammatory factors and bone metabolism factors,effectively inhibited the expression of p-lKKafi,p-lA:Ba,and p-p65 proteins.In vivo,AU relieved joint inflammation,reduced related inflammatory factors,and inhibited NF-/cB signaling.It could be used to treat RA-related synovial inflammation and bone destruction through the NF-/cB pathway.