ROLE OF INTERLEUKIN-4 AND INTERLEUKIN-10 IN MURINE COLLAGEN-INDUCED ARTHRITIS - PROTECTIVE EFFECT OF INTERLEUKIN-4 AND INTERLEUKIN-10 TREATMENT ON CARTILAGE DESTRUCTION

Objective. To examine the role of endogenous interleukin-4 (IL-4) and interleukin-10 (IL-10) and the therapeutic effect of the addition of I L-4 and IL-10 in early and established murine collagen-induced arthrit is (CIA). Methods. Murine recombinant IL-4, IL-10, or the combination was given intraperitoneally twice daily from the day of arthritis onse t 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 vi sually by macroscopic scoring. Histology and reverse transcription-pol ymerase 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 amelior ation was found with the combination. This cooperative effect was note d after early treatment but also occurred when the start of treatment was delayed until 1 week after onset. Apart from suppression of macros copic signs of inflammation, combined treatment with IL-4/IL-10 also r educed cellular infiltrates in the synovial tissue and caused pronounc ed protection against cartilage destruction. Moreover, levels of mRNA for tumor necrosis factor alpha (TNF alpha) and IL-1 were highly suppr essed both in the synovial tissue and in the articular cartilage. In c ontrast, levels of IL-1 receptor antagonist (IL-1Ra) mRNA remained ele vated, which suggests that the mechanism of protection may be related to suppressed production of TNF alpha and IL-1, with concomitant up-re gulation 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 combina tion of anti-IL-4 and anti-IL-10 antibodies, although anti-IL-4 alone was without effect. Conclusion. Our data are consistent with a dominan t role of IL-10 in the natural suppression of arthritis expression, wh ereas combined treatment with IL-4 and IL-10 appears of potential ther apeutic value, not only at the onset, but also in established arthriti s.