Journal
ARTHRITIS AND RHEUMATISM
Volume 60, Issue 3, Pages 678-685Publisher
WILEY
DOI: 10.1002/art.24299
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Funding
- Korean government (Korea Science and Engineering Foundation MOST) [R01-2006-000-10837-0]
- Korea Research Foundation MOEHRD
- Ministry of Education and Human Resources Development in Korea
- National Research Foundation of Korea [R01-2006-000-10837-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Objective. 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. Methods. 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. Results. IL-32 levels were high in RA SF com-pared with OA SF. Furthermore, RA FLS expressed and secreted IL-32 when stimulated with tumor necrosis factor a (TNF alpha). TNF alpha-induced expression of IL-32 was significantly suppressed, in a dose-dependent manner, by inhibitors of Syk, protein kinase CS (PKC delta), and JNK and by knockdown of these kinases and c-Jun with siRNA. We also observed that PKC delta 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 PKCS. Conclusion. 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/PKC delta-mediated signaling events.
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