Alpha-Defensin-1 Induces Il-6 And Mmp-1 Expression In Rheumatoid Fibroblast-Like Synoviocytes Via Erk And/Orjnk Signaling Pathway

Background Fibroblast-like synoviocytes (FLS) play an essential role in the pathophysiology of rheumatoid arthritis (RA). Neutrophils play an important role in overt inflammation in RA and are the most abundant cell type in the acute synovial effusion of RA patients. α-defensin-1 is released into the extracellular milieu from neutrophils during inflammation. Little is known of the role of α-defensin-1 for the development of joint inflammation in RA. Objectives We assessed the concentration of α-defensin-1 in synovial fluid (SF) of RA patients and osteoarthritis (OA) patients. We also investigated the effect of α-defensin-1 on the expression of IL-6, IL-8, MMP-1 and MMP-3 and the signal transduction mechanisms responsible for α-defensin-1-induced IL-6, IL-8 and MMPs expression in RA FLS. Methods The concentrations of SF α-defensin-1 from 51 RA patients and 21 OA patients were measured using ELISA. Real-time PCR was performed to investigate the effect of α-defensin-1 on IL-6, IL-8, and MMPs mRNA expression in RA FLS (n=5). Cell lysates were analyzed for mitogen-activated protein (MAP) kinases activity by Western blot analysis (n=3). The critical pathways for α-defensin-1-induced IL-6, IL-8, and MMPs expression were determined by using JNK (SP600125, 10 uM) or ERK inhibitor (U0126, 10 uM). Results The SF α-defensin-1 concentration was significantly increased in RA patients compared to OA patients (39.3±3.5 vs. 18.0±5.6 ng/ml, p=0.002). IL-6, IL-8, MMP-1 and MMP-3 mRNA expressions were significantly increased (13.34±22.89-fold, 2.89±1.49-fold, 15.17±7.15-fold, and 4.10±1.56-fold increase, respectively; all p Conclusions α-defensin-1-induced IL-6 and MMP-1 productions were dependent on activation of MAP kinase JNK and/or ERK while α-defensin-1-induced IL-8 and MMP-3 expression appears to have salvage pathways other than MAP kinase pathway. These data provide new insight regarding the mechanism by which α-defensin-1 participates in joint inflammation and destruction in RA and a rationale for targeting α-defensin-1 as a new therapeutic option for RA. Disclosure of Interest None Declared