PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) regulates IL-6-STAT3 signaling to reduce neutrophil infiltration into the synovium of arthritic joints

Abstract

Abstract Inappropriate regulation of leukocyte trafficking can lead to impaired neutrophil clearance and increased tissue damage from the accumulation of neutrophil-secreted proteases and reactive oxygen species at the site of inflammation. In this study, we have discovered that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) regulates the activity of signal transducer and activator of transcription 3 (STAT3), which is a master regulator of IL-6 expression. PLAG has been isolated from the antlers of Sika deer (Cervus nippon Temminck), which were known to have immunosuppressive and anti-arthritic activities. PLAG induced a significant decrease of IL-6 production in a macrophage cell line, RAW264.7, and rheumatoid arthritis-fibroblast-like synoviocyte (RA-FLS) via the regulation of STAT3 signaling. IL-6, a multifunctional pro-inflammatory cytokine, plays a critical role in the pathogenesis of joint and systemic inflammation in RA. In collagen-induced arthritis (CIA) mouse model, arthritic symptoms were recapitulated with an increase of IL-6 in the synovium, which was recuperated by the treatment of PLAG to the level comparable with commercial therapeutics (such as Remicade or Methotrexate). When the joint tissues were stained with neutrophil-specific antibodies, PLAG significantly reduced the infiltration of neutrophils into the joint synovium of CIA mouse. Therefore, PLAG inhibits the infiltration of destructive neutrophils into inflammatory sites, and can be utilized as a therapeutic agent for the treatment of sustained inflammation and joint destruction.