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

SUMMARY 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/μg total RNA; ranged from 0·1 pg to 96 pg IL‐17R mRNA/μg 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‐α and GRO‐β. An anti‐IL‐17 antibody blocked these effects of IL‐17. The MAPK p38 appears necessary for the regulation of IL‐8, GRO‐α and GRO‐β 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‐α and GRO‐β 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.