Rheumatoid Arthritis Basic Science Studies
Tumor necrosis factor α–induced interleukin-32 is positively regulated via the Syk/protein kinase Cδ/JNK pathway in rheumatoid synovial fibroblasts
Version of Record online: 26 FEB 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 3, pages 678–685, March 2009
How to Cite
Mun, S. H., Kim, J. W., Nah, S. S., Ko, N. Y., Lee, J. H., Kim, J. D., Kim, D. K., Kim, H. S., Choi, J. D., Kim, S. H., Lee, C. K., Park, S. H., Kim, B. K., Kim, H. S., Kim, Y. M. and Choi, W. S. (2009), Tumor necrosis factor α–induced interleukin-32 is positively regulated via the Syk/protein kinase Cδ/JNK pathway in rheumatoid synovial fibroblasts. Arthritis & Rheumatism, 60: 678–685. doi: 10.1002/art.24299
- Issue online: 26 FEB 2009
- Version of Record online: 26 FEB 2009
- Manuscript Accepted: 7 NOV 2008
- Manuscript Received: 3 JUN 2008
- Korean government
- Korea Science and Engineering Foundation MOST. Grant Number: R01-2006-000-10837-0
- Korea Research Foundation MOEHRD grant funded through the Regional Research Universities Program/Chungbuk BIT Research-Oriented University Consortium
- Ministry of Education and Human Resources Development in Korea (Second Phase BK21 Program)
Interleukin-32 (IL-32) is a recently discovered cytokine that appears to play a critical role in human rheumatoid arthritis (RA). It is highly expressed in synovium and fibroblast-like synoviocytes (FLS) from RA patients, but not in patients with osteoarthritis (OA). This study was undertaken to assess IL-32 levels in RA synovial fluid (SF) and to investigate the secretion and regulation of IL-32 in RA FLS.
FLS and SF were obtained from the joints of RA patients. The secretion and expression of IL-32 and activation of signaling molecules were examined by enzyme-linked immunosorbent assay, immunoblotting, immunoprecipitation, reverse transcriptase–polymerase chain reaction, and small interfering RNA (siRNA) transfection.
IL-32 levels were high in RA SF compared with OA SF. Furthermore, RA FLS expressed and secreted IL-32 when stimulated with tumor necrosis factor α (TNFα). TNFα-induced expression of IL-32 was significantly suppressed, in a dose-dependent manner, by inhibitors of Syk, protein kinase Cδ (PKCδ), and JNK and by knockdown of these kinases and c-Jun with siRNA. We also observed that PKCδ mediated the activation of JNK and c-Jun, and experiments using specific inhibitors and siRNA demonstrated that Syk was the upstream kinase for the activation of PKCδ.
The present findings suggest that IL-32 may be a newly identified prognostic biomarker in RA, thereby adding valuable knowledge to the understanding of this disease. The results also demonstrate that the production of IL-32 in RA FLS is regulated by Syk/PKCδ-mediated signaling events.