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Abstract Number: 1181

The Role of á-Defensin-1 and Its Signal Transduction Mechanisms in the Production of IL-6, IL-8 and MMPs in Rheumatoid Fibroblast-Like Synoviocytes

Joong Kyong Ahn1, Bo Huang2, Eun-Jung Park2, Jiwon Hwang3, Jaejoon Lee2, Chan Hong Jeon4, Eunmi Koh2 and Hoon-Suk Cha5, 1Department of Medicine, Kangbuk Samsung hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea, 2Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, 3Department of Medicine,Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, 4Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, South Korea, 5Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: pathogenesis, rheumatoid arthritis

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Session Information

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.


Disclosure:

J. K. Ahn,
None;

B. Huang,
None;

E. J. Park,
None;

J. Hwang,
None;

J. Lee,
None;

C. H. Jeon,
None;

E. Koh,
None;

H. S. Cha,
None.

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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/

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