Fibroblast-like synoviocytes (FLS) play a pivotal role in the pathogenesis of
rheumatoid arthritis (RA) through aggressive proliferation and invasion, and certain proinflammatory
cytokines may affect synoviocyte proliferation. To evaluate whether
interleukin-21 (IL-21) could promote proliferation and proinflammatory
cytokine production by RA-FLS, immunohistochemistry and immunoblotting were performed to observe the expression of
IL-21 receptor (IL-21R) in synovial tissues and FLS from RA and
osteoarthritis (OA) patients. The MTS assay was used to analyse RA-FLS proliferation. The concentrations of
IL-6 and tumour
necrosis factor-α (TNF-α) in culture supernatants were determined by
enzyme-linked
immunosorbent assay (ELISA). The signalling pathways triggered by
IL-21 were characterized by immunoblotting. IL-21R was upregulated in the synovial tissues and FLS of RA patients as compared with OA patients.
IL-21 stimulated RA-FLS proliferation and promoted the production of TNF-α and
IL-6 and blockade of IL-21/IL-21R pathway with IL-21R.Fc attenuated IL-21-induced proliferation and secretion of TNF-α and
IL-6. Moreover,
IL-21 induced activation of the ERK1/2, PI3K/AKT and STAT3 pathways, and blockade of these pathways attenuated IL-21-induced proliferation and secretion of TNF-α and
IL-6. These results suggest that
IL-21 could promote RA-FLS proliferation and production of proinflammatory
cytokines. Therefore, therapeutic strategies targeting
IL-21 might be effective for the treatment of RA.