Interleukin-1 receptor antagonist intervenes in signaling between different types of synoviocytes in rats with adjuvant arthritis
Abstract
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-α) 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-α 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-α (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:
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-α) 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-α 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-α (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.