Interleukin-17 increases the expression of Toll-like receptor 3 via the STAT3 pathway in rheumatoid arthritis fibroblast-like synoviocytes.
We examined the effect of interleukin-17 (IL-17) on the expression of Toll-like receptors (TLRs) in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). We investigated the region downstream of IL-17 for TLR expression. We also investigated the downstream signals responsible for the effect of IL-17 in TLR expression. Levels of IL-17 protein in the serum and synovial fluid of RA and OA patients were measured by ELISA. The IL-17 mRNA expression in peripheral blood mononuclear cells and synovial fluid mononuclear cells was measured by RT-PCR. RA and OA FLS were incubated with IL-17 and/or IL-23 for 24 hr. To block the signal transducer and activator of transcription 3 (STAT3) pathway, FLS were treated with S3I-201 before incubation with IL-17 and IL-23. Synovial tissue samples from RA and OA patients were stained with antibodies to IL-17, TLR2, TLR3, TLR4, STAT3 and phospho-STAT3. Levels of IL-17 protein were higher in the serum and synovial fluid from RA patients compared with those from OA patients. The IL-17 mRNA expression in synovial fluid monocytes was also higher in RA than in OA patients. Immunohistochemical staining showed greater expression of IL-17, TLR2, TLR3 and TLR4 in synovial samples from RA compared with OA patients. Interleukin-17 increased the expression of TLR2, TLR3 and TLR4 in RA FLS; IL-23 augmented the IL-17-induced expression of TLR2, TLR3 and TLR4 in RA FLS. Blocking STAT3 with S3I-201 reduced IL-17-induced TLR3 expression in RA FLS. Our results suggest that IL-17 is a major cytokine in pathogenesis on RA. The IL-17 influences the innate immune system by increasing the synovial expression of TLR2, TLR3 and TLR4. We may control TLR3 expression via the STAT3 pathway in RA FLS.
Rheumatism Research Centre, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea.
Seon-Yeong
SY
Lee
Bo-Young
BY
Yoon
Ju-In
JI
Kim
Yang-Mi
YM
Heo
Yun-Ju
YJ
Woo
Sung-Hwan
SH
Park
Ho Youn
HY
Kim
Sung-Il
SI
Kim
Mi-La
ML
Cho
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation
D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4
Toll-like receptors; human; interleukin-17; rheumatoid arthritis; signal transducer and activator of transcription 3; synovial fibroblasts