Joosten Leo A B, Helsen Monique M A, van de Loo Fons A J, van den Berg Wim B
University Hospital Nijimegen, Nijimegen, The Netherlands.
Arthritis Rheum. 2008 Feb;58(2 Suppl):S110-22. doi: 10.1002/art.23363.
To examine the role of tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta in collagen-induced arthritis (CIA), immediately after onset and during the phase of established arthritis.
Male DBA/1 mice with collagen-induced arthritis were treated with antibodies against murine TNF alpha and IL-1 alpha/beta at different time points of the disease. IL-1 receptor antagonist (IL-1Ra) was administered using Alzet osmotic minipumps. The effect of anticytokine treatment was monitored by visual scoring. Histology and cytokine reverse transcription polymerase chain reaction (RT-PCR) analyses were performed at the end of the treatment period.
Anti-TNF alpha treatment showed efficacy shortly after onset of the disease, but had little effect on fully established CIA. Histologic analysis after early treatment revealed that anti-TNF alpha significantly reduced joint pathology, as determined by infiltration of inflammatory cells and cartilage damage. Anti-IL-1 alpha/beta treatment ameliorated both early and full-blown CIA. This clear suppression of established arthritis was confirmed by administration of high doses of IL-1Ra. Dose-response experiments showed that a continuous supply of 1 mg/day was needed for optimal suppression. Histologic analysis showed markedly reduced cartilage destruction both in the knee and the ankle joints. Autoradiography demonstrated full recovery of chondrocyte synthetic function of articular cartilage. In addition, we found that the IL-1 beta isoform plays a dominant role in established CIA. Profound suppression of CIA was observed with anti-IL-1 beta, although elimination of both IL-1 alpha and IL-1 beta still gave better protection. Analysis of messenger RNA with RT-PCR revealed that IL-1 beta was highly upregulated in synovium and cartilage at late stages of CIA, whereas anti-IL-1 beta treatment markedly reduced IL-1 beta message in the synovium.
The present study identified different TNF alpha/IL-1 dependencies in various stages of CIA and revealed that blocking of TNF alpha does not necessarily eliminate IL-1. Continuous, high doses of IL-1Ra are needed to block CIA.
研究肿瘤坏死因子α（TNFα）、白细胞介素-1α（IL-1α）和白细胞介素-1β（IL-1β）在胶原诱导性关节炎（CIA）发病即刻及关节炎已确立阶段所起的作用。
用抗小鼠TNFα和IL-1α/β抗体在疾病的不同时间点治疗胶原诱导性关节炎的雄性DBA/1小鼠。使用Alzet渗透微型泵给予白细胞介素-1受体拮抗剂（IL-1Ra）。通过视觉评分监测抗细胞因子治疗的效果。在治疗期结束时进行组织学和细胞因子逆转录聚合酶链反应（RT-PCR）分析。
抗TNFα治疗在疾病发病后不久显示出疗效，但对完全确立的CIA几乎没有影响。早期治疗后的组织学分析显示，抗TNFα显著减轻了关节病变，这是通过炎症细胞浸润和软骨损伤来确定的。抗IL-1α/β治疗改善了早期和严重的CIA。高剂量IL-1Ra的给药证实了对已确立关节炎的明显抑制作用。剂量反应实验表明，最佳抑制需要每天持续供应1毫克。组织学分析显示，膝关节和踝关节的软骨破坏均明显减轻。放射自显影显示关节软骨的软骨细胞合成功能完全恢复。此外，我们发现IL-1β亚型在已确立的CIA中起主导作用。用抗IL-1β观察到CIA的显著抑制，尽管消除IL-1α和IL-1β两者仍能提供更好的保护。用RT-PCR分析信使RNA显示，在CIA晚期，IL-1β在滑膜和软骨中高度上调，而抗IL-1β治疗显著降低了滑膜中的IL-1β信使水平。
本研究确定了CIA不同阶段中TNFα/IL-1的不同依赖性，并表明阻断TNFα不一定能消除IL-1。需要持续高剂量的IL-1Ra来阻断CIA。
