Acta Pharmacologica Sinica 2006 January; 27 (1): 111-118; doi: 10.1111/j.1745-7254.2006.00234.x

Aim: To investigate the mechanisms of interleukin-1 receptor antagonist (IL-1ra) in the treatment of adjuvant arthritis (AA).

Methods:AA was induced in rats by treatment with Freund's complete adjuvant (FCA). Rats were given an intracutaneous injection of IL-1ra (2.5, 10, 40 mg/kg, 3 times per day) from d 14 to d 21 after immunization. Synoviocyte proliferation and the activity of IL-1 were determined by using MTT assay. Tumor necrosis factor alpha (TNF-a) and prostaglandin E₂ (PGE₂) concentrations were measured by radioimmunoassay. The ultrastructure of synoviocytes was observed by using a transmission electron microscope. Phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulating kinase (ERK) and p38 kinase were detected by Western blot analysis.

Results: IL-1ra (10 and 40 mg/kg, ic, d 14-21) modulated the secondary inflammatory reaction (P<0.01), ultrastructure of synoviocytes and mitogen-activated protein kinase (MAPK) phosphorylation in AA rats. The administration of IL-1ra (10 and 40 mg/kg, ic, d 14-21) in AA rats significantly decreased the production of IL-1, PGE₂ and TNF-a by macrophage-like synoviocytes (MLS) (P<0.01). IL-1ra (2.5 mg/kg) also decreased the production of PGE₂ (P<0.01) and TNF-a (P<0.05) by MLS in AA rats. The increased phosphorylation of MAPK and cell proliferation in fibroblast-like synoviocytes (FLS) stimulated by supernatants of MLS in AA rats was also inhibited by IL-1ra (10 and 40 mg/kg, ic, d 14-21).

Conclusion: IL-1ra has anti-inflammatory effects because it modulates the ultrastructure of synoviocytes, decreases the production of pro-inflammatory mediators by MLS, and inhibits the phosphorylation of MAPK in FLS.

Keywords: interleukin-1 receptor; experimental arthritis; mitogen-activated protein kinase; synovial membrane