Role of interleukin‐4 and interleukin‐10 in murine collagen‐induced arthritis. Protective effect of interleukin‐4 and interleukin‐10 treatment on cartilage destruction

Abstract

Objective. To examine the role of endogenous interleukin‐4 (IL‐4) and interleukin‐10 (IL‐10) and the therapeutic effect of the addition of IL‐4 and IL‐10 in early and established murine collagen‐induced arthritis (CIA). Methods. Murine recombinant IL‐4, IL‐10, or the combination was given intraperitoneally twice daily from the day of arthritis onset up to 7–10 days of CIA in DBA/1 mice. Anti‐IL‐4, anti–IL‐10, or both antibodies were given intraperitoneally before or after the onset of CIA. The effect of cytokine or anticytokine treatment was monitored visually by macroscopic scoring. Histology and reverse transcription‐polymerase chain reaction (RT‐PCR) analyses were performed at the end of the treatment period. Results. IL‐4 alone did not provoke any effect, IL‐10 slightly suppressed the arthritis, but a more pronounced amelioration was found with the combination. This cooperative effect was noted after early treatment but also occurred when the start of treatment was delayed until 1 week after onset. Apart from suppression of macroscopic signs of inflammation, combined treatment with IL‐4/IL‐10 also reduced cellular infiltrates in the synovial tissue and caused pronounced protection against cartilage destruction. Moreover, levels of mRNA for tumor necrosis factor α (TNFα) and IL‐1 were highly suppressed both in the synovial tissue and in the articular cartilage. In contrast, levels of IL‐1 receptor antagonist (IL‐1Ra) mRNA remained elevated, which suggests that the mechanism of protection may be related to suppressed production of TNFα and IL‐1, with concomitant up‐regulation of the IL‐1Ra/IL‐1 balance. However, accelerated onset of CIA and increased severity could be achieved with neutralizing anti–IL‐10 antibodies. This expression could be further optimized with a combination of anti–IL‐4 and anti–IL‐10 antibodies, although anti–IL‐4 alone was without effect. Conclusion. Our data are consistent with a dominant role of IL‐10 in the natural suppression of arthritis expression, whereas combined treatment with IL‐4 and IL‐10 appears of potential therapeutic value, not only at the onset, but also in established arthritis.