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. 2000 Nov;59(Suppl 1):i81–i84. doi: 10.1136/ard.59.suppl_1.i81

Arguments for interleukin 1 as a target in chronic arthritis

W B van den Berg
PMCID: PMC1766623  PMID: 11053095

Abstract

Tumour necrosis factor (TNF) and interleukin 1 (IL1) are considered as master cytokines in chronic, destructive arthritis. Therapeutic approaches in rheumatic arthritis (RA) patients so far mainly focused on TNF. Although TNF is a major inflammatory mediator in RA and a potent inducer of IL1, anti-TNF treatment is not effective in all patients, nor does it fully control the arthritic process in affected joints of good responders. Analysis of cytokine patterns in early synovial biopsy specimens of RA patients reveals prominent TNF staining in 50% of the patients, whereas IL1b staining was evident in 100%. This argues that TNF independent IL1 production occurs in some of the patients. Studies in a range of experimental arthritis models in mice make it clear that TNF is involved in early joint swelling. However, TNF alone is not arthritogenic nor destructive and exerts its arthritogenic potential through IL1 induction. Intriguingly, TNF independent IL1 production is found in many models. Its relevance is further underlined by the greater efficacy of anti-IL1 treatment as compared with anti-TNF treatment and the total lack of chronic, erosive arthritis in IL1b deficient mice. IL1b is not necessarily involved in early joint swelling, but is a crucial mediator in chronic arthritis and cartilage erosion in all models studied so far. This makes ILb an attractive target in chronic, destructive arthritis.



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Figure 1  .

Figure 1  

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IL1b levels in tissue washouts six hours after injection of SCW fragments into the knee joint of mice. The first set depicts IL1 levels in control and anti-TNFa treated mice (see also van den Berg6). The second set depicts values in control and TNF-/- mice. Although some reduction is consistently noted in TNF -/- mice, it does not reach statistical significance, implying that most of the IL1 is produced in a TNF independent fashion.

Figure 2  .

Figure 2  

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Simplified version of cytokine involvement in osteoclast activation.

Figure 3  .

Figure 3  

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Potential pathways of TNF overproduction. Note that general T cell/macrophage triggering, as studied in arthritis models, gives rise to both TNF and IL1, with considerable TNF independent IL1 production, and extreme skewing to IL1 when immune complexes are used as stimulus.

Figure 4  .

Figure 4  

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Amplifying elements in erosive processes. Immune complexes generate high levels of IL1 and through Fc interaction also provide additional mediators to activate pro-MMPs (metalloproteinases). T cells may be involved in enhanced bone erosion through TNF, IL17 and direct OPG-L production. T cells come close to the bone at erosion sites. IL17 also promotes cartilage erosion, a role of OPG-L in this remains to be seen.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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