Session Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Background/Purpose: Fibroblast-like synoviocytes (FLS) play an essential role in the pathophysiology of rheumatoid arthritis (RA). Also, neutrophils are the most abundant cell type of synovial fluid (SF) in flare-up of RA patients, suggesting that this cell plays an important role in overt inflammation in RA. α-defensin-1 is released into the extracellular milieu from neutrophils during inflammation. However, little is known of the role of α-defensin-1 in RA. We investigated the effect of α-defensin-1 on the expression of IL-6, IL-8, and MMPs and the signal transduction mechanisms responsible for these expressions in RA FLS.
Methods: The concentrations of SF α-defensin-1 from 51 RA patients and 21 OA patients were measured using ELISA. In rheumatoid FLS, IL-6, IL-8, and MMPs mRNA expression was examined using real-time PCR. The activation of signaling molecules was evaluated by Western blotting and EMSA.
Results: 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 in RA FLS after α-defensin-1 stimulation compared to control (n=5)(all p <0.05). JNK and ERK were significantly phosphorylated in FLS stimulated with α-defensin-1 compared to control (n=3)(25.2±3.4-fold, p=0.008 and 1.42±0.24-fold, p=0.05, respectively), while no significant change was found in p38 activity. Treatment of RA FLS with ERK inhibitor prior to α-defensin-1 stimulation significantly resulted in approximately 71% and 98% reduction, respectively, in IL-6 and MMP-1 production compared with control (p <0.05 for each). Blocking JNK pathway significantly suppressed α-defensin-1-induced MMP-1 production by approximately 73% compared with control (p<0.01). α-defensin-1-induced IL-8 expression was reduced by approximately 68% and 52% by inhibition of ERK and JNK, respectively. Also, α-defensin-1-induced MMP-3 expression was reduced by approximately 22% and 50% by ERK and JNK inhibitor, respectively. However, these differences did not reach statistical significance. In addition, there was a significant induction of NF-κB DNA binding activity in response to the stimulation of α-defensin-1 in rheumatoid FLS.
Conclusion: Our results are notable to suggest that increased SF α-defensin-1 released mainly by neutrophils can induce the expression of IL-6 and MMP-1 in rheumatoid FLS and these processes were dependent on the regulation of JNK and/or ERK and NF-κB pathway. These data provide new insight regarding the mechanism by which α-defensin-1 participates in joint inflammation and destruction in RA.
J. K. Ahn,
E. J. Park,
C. H. Jeon,
H. S. Cha,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-a-defensin-1-and-its-signal-transduction-mechanisms-in-the-production-of-il-6-il-8-and-mmps-in-rheumatoid-fibroblast-like-synoviocytes/