Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis

被引:99
作者
Kehlen, A [1 ]
Thiele, K [1 ]
Riemann, D [1 ]
Langner, J [1 ]
机构
[1] Univ Halle Wittenberg, Inst Med Immunol, D-06097 Halle An Der Saale, Germany
关键词
chemokine; IL-17; receptor; rheumatoid arthritis;
D O I
10.1046/j.1365-2249.2002.01782.x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4(+) CD45RO(+) memory T cells. Overproduction of IL-17 was detected in the synovium of patients with rheumatoid arthritis (RA) compared to patients with osteoarthritis. In contrast to the restricted expression of IL-17, the IL-17 receptor (IL-17R/CDw217) is expressed ubiquitously. Using a real-time RT-PCR assay, we detected similar absolute levels of IL-17R mRNA expression in fibroblast-like synoviocytes (SFC) from patients with RA (mean 9 pg/mug total RNA; ranged from 0.1 pg to 96 pg IL-17R mRNA/mug total RNA) compared to synoviocytes of non-RA patients. Analysis of the IL-17R surface expression confirmed the results obtained for IL-17R mRNA expression. Exposure of SFC to IL-17 led to a mRNA induction of CXC chemokines IL-8, GRO-alpha and GRO-beta. An anti-IL-17 antibody blocked these effects of IL-17. The MAPK p38 appears necessary for the regulation of IL-8, GRO-alpha and GRO-beta expression as shown by inhibition with SB203580. The inhibitors genistein (tyrosine kinase inhibitor) and calphostin C (inhibitor of protein kinase C) reduced significantly the IL-17-stimulated mRNA expression of IL-8, GRO-alpha and GRO-beta in SFC, whereas PD98059 (inhibitor of MEK-1/2) was without effect. Pharmacological drugs used in therapy of RA, such as cyclosporin and methotrexate, induced a fourfold increase of IL-17R mRNA expression and augmented the IL-17-stimulated IL-8 expression. Our results support the hypothesis that IL-17/IL-17R may play a significant role in the pathogenesis of RA contributing to an unbalanced production of cytokines as well as participating in connective tissue remodelling.
引用
收藏
页码:539 / 546
页数:8
相关论文
共 46 条
[21]  
2-#
[22]   Interleukin-17 stimulates the expression of IκBα mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines [J].
Kehlen, A ;
Thiele, K ;
Riemann, D ;
Rainov, N ;
Langner, J .
JOURNAL OF NEUROIMMUNOLOGY, 1999, 101 (01) :1-6
[23]  
KOCH AE, 1995, J INVEST MED, V43, P28
[24]  
Laan M, 1999, J IMMUNOL, V162, P2347
[25]   Methotrexate suppresses NF-κB activation through inhibition of IκBα phosphorylation and degradation [J].
Majumdar, S ;
Aggarwal, BB .
JOURNAL OF IMMUNOLOGY, 2001, 167 (05) :2911-2920
[26]  
Martel-Pelletier J, 1999, ARTHRITIS RHEUM-US, V42, P2399, DOI 10.1002/1529-0131(199911)42:11<2399::AID-ANR19>3.0.CO
[27]  
2-Y
[28]   Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides [J].
Morabito, L ;
Montesinos, MC ;
Schreibman, DM ;
Balter, L ;
Thompson, LF ;
Resta, R ;
Carlin, G ;
Huie, MA ;
Cronstein, BN .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (02) :295-300
[29]  
NAVARRETE SA, 1997, IMMUNOL LETT, V58, P53
[30]  
RICHMOND A, 1984, J CELL BIOCHEM, V36, P185