Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis - Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction
Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis - Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction
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DOI：
10.1002/art.1780400209
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发表时间：
1997-02-01
影响因子：
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通讯作者：
vandenBerg, WB
中科院分区：
文献类型：
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作者：
Joosten, LAB;Lubberts, E;vandenBerg, WB
Objective.研究内源性白细胞介素4（IL-4）和白细胞介素10（IL-10）在小鼠胶原诱导性关节炎（CIA）早期和建立过程中的作用，以及IL-4和IL-10对CIA的治疗作用。在DBA/1小鼠中，从关节炎发作之日至CIA 7-10天，每天两次腹膜内给予鼠重组IL-4、IL-10或其组合。抗IL-4，抗IL-10，或两种抗体在CIA发病前或发病后腹腔内给药。细胞因子或抗细胞因子处理的效果通过肉眼评分进行视觉监测。治疗结束时进行组织学和逆转录-聚合酶链反应（RT-PCR）分析。单独的IL-4没有引起任何效果，IL-10轻微抑制关节炎，但发现联合使用更明显的改善。这种协同效应在早期治疗后观察到，但也发生在治疗开始延迟至发病后1周时。除了抑制肉眼可见的炎症体征外，IL-4/IL-10联合治疗还减少了滑膜组织中的细胞浸润，并对软骨破坏产生了明显的保护作用。此外，在滑膜组织和关节软骨中，肿瘤坏死因子α（TNF α）和IL-1的mRNA水平均受到高度抑制。相比之下，IL-1受体拮抗剂（IL-1 Ra）mRNA水平保持升高，这表明保护机制可能与TNF α和IL-1的产生受到抑制有关，同时上调IL-1 Ra/IL-1平衡。然而，使用中和抗IL-10抗体可以实现CIA的加速发作和增加的严重程度。抗IL-4抗体和抗IL-10抗体的组合可以进一步优化这种表达，尽管单独的抗IL-4抗体没有效果。我们的数据与IL-10在自然抑制关节炎表达中的主导作用一致，而IL-4和IL-10的联合治疗似乎具有潜在的治疗价值，不仅在发病时，而且在已建立的关节炎中。
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.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.