Immune Netw.  2003 Dec;3(4):310-319. 10.4110/in.2003.3.4.310.

Regulation of Interleukin-17 Production in Patients with Rheumatoid Arthritis by Phosphoinositide 3-kinase (PI3K)/ Akt and Nuclear Factor KappaB (NF-kappaB) Dependent Signal Transduction Pathway

  • 1Rheumatism Research Center, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul, Korea.


Inflammatory mediators has been recognized as an important role in the pathogenesis of rheumatoid arthritis (RA). IL-17 is increasingly recognized as an important regulator of immune and inflammatory responses, including induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence of the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. However, the signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in the regulation of IL-17 production in RA. PBMC were separated from RA (n=24) patients, and stimulated with various agents (anti CD3, anti CD28, PHA, ConA, IL-15). IL-17 levels were determined by sandwich ELISA and RT-PCR. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody, PHA, IL-15 or MCP-1 (P<0.05). ConA also strongly induced IL-17 production (P<0.001), whereas TNF-alpha, IL-1beta, IL-18 or TGF-beta did not. IL-17 was detected in the PBMC of patients with osteoarthritis (OA) but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K-Akt pathway and activation of the PI3K-Akt pathway resulted in a pronounced augmentation of nuclear factor kappaB (NF-kappaB). IL-17 production by activated PBMC in RA is completely or partially blocked in the presence of NF-kappaB inhibitor PDTC and PI3K- Akt inhibitor, wortmannin and LY294002, respectively. Whereas the inhibition of AP-1 and extracellular signal-regulated kinase (ERK)1/2 did not affect IL-17 production. These results provide new insight into that PI3K/Akt and NF-kappaB dependent signal transduction pathway could be involved in the overproduction of key inflammatory cytokine, IL-17 in rheumatoid arthritis.


Interleukin-17; rheumatoid arthritis; PI3K/Akt pathway; NF-kappaB; PBMC
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