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 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 alpha (TNF alpha) 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 TNF alpha 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.


CONCLUSIONS
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.
Joosten
L A
LA
University Hospital Nijmegen, The Netherlands.
Lubberts
E
E
Durez
P
P
Helsen
M M
MM
Jacobs
M J
MJ
Goldman
M
M
van den Berg
W B
WB
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D002357:Cartilage Diseases / Q000517:prevention & control; D002417:Cattle; D003094:Collagen / Q000633:toxicity*; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000502:physiology* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000502:physiology* / Q000627:therapeutic use; D007719:Knee Joint / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D003094:Collagen