Tumor necrosis factor α–induced interleukin‐32 is positively regulated via the Syk/protein kinase Cδ/JNK pathway in rheumatoid synovial fibroblasts
2009; Wiley; Volume: 60; Issue: 3 Linguagem: Inglês
10.1002/art.24299
ISSN1529-0131
AutoresSe Hwan Mun, Jie Wan Kim, Seong Su Nah, Na Young Ko, Jun‐Ho Lee, Ju Dong Kim, Do Kyun Kim, Hyuk Soon Kim, Ji Da Choi, Soo Hyun Kim, Chang Keun Lee, Seung Hwa Park, Bo Kyung Kim, Hyung Sik Kim, Young Mi Kim, Wahn Soo Choi,
Tópico(s)Pharmacological Effects of Natural Compounds
ResumoAbstract 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 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. 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/PKCδ‐mediated signaling events.
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