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. 1999 Nov;58(Suppl 1):I40–I48. doi: 10.1136/ard.58.2008.i40

Role of tumour necrosis factor α in experimental arthritis: separate activity of interleukin 1β in chronicity and cartilage destruction

W B van den Berg, L Joosten, G Kollias, F A J van de Loo
PMCID: PMC1766568  PMID: 10577972

Abstract

Chronic arthritis is characterised by persistent joint inflammation and concomitant joint destruction. Using murine arthritis models and neutralising antibodies as well as cytokine specific knockout conditions, it was found that tumour necrosis factor α (TNFα) is important in early joint swelling. Membrane bound TNFα is sufficient to drive this aspect of inflammation as well as the acute cellular infiltrate in the synovial tissue. Interleukin 1 (IL1) is not necessarily a dominant cytokine in early joint swelling, but has a pivotal role in sustained cellular infiltration and erosive cartilage damage. TNFα independent IL1 production is a prominent feature in murine arthritis models. These observations provide evidence for potential uncoupling of joint inflammation and erosive changes, implying that both cytokines need to be targeted to achieve optimal treatment.



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Figure 1  .

Figure 1  

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Treatment of collagen arthritis with TNF binding protein or anti-IL1α+β antibodies, starting at various days after onset of arthritis (arrows). Note the loss of effect in established disease with TNFbp and the continued effect of anti-IL1 (see also references 22 and 30).

Figure 2  .

Figure 2  

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COMP levels in the serum at day 38 of collagen arthritis. After treatment with TNFbp no reduction is seen, whereas reduction to normal levels (line) is observed after anti-IL1α+β treatment.

Figure 3  .

Figure 3  

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Dose dependent suppression of joint swelling with anti-TNFα or TNFbp. Start of systemic treatment shortly before induction of SCW arthritis, measurements of joint swelling at day 2. (See reference 34 for further reading).

Figure 4  .

Figure 4  

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Joint swelling at days 1 and 2 after induction of SCW arthritis in knockouts and their respective controls (NN for IL1β -/-, WT for TNFα -/-). Note the TNFα dependency of joint swelling. Similar studies in mTNFki, reflecting knockin of mTNFα in TNF-/- mice, reveal that mTNFα is sufficient to drive swelling.

Figure 5  .

Figure 5  

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Cellular infiltrate is markedly reduced in SCW arthritis (day 7) in TNFα -/- mice (B). However, the Safranin O staining shows that there is considerable loss of proteoglycans (reduced staining) in both control (A) and TNF-/- (B).

Figure 6  .

Figure 6  

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Proteoglycan depletion as measured on histological sections (see fig 5) stained with Safranin O at days 4 and 7 after induction of SCW arthritis. Scoring is semiquantitative on a scale of 0-3. Note the significant reduction of depletion (* p < 0.01) only in IL1β-/- mice.

Figure 7  .

Figure 7  

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Chronic relapsing SCW arthritis induced by repeated injection of SCW fragments in the knee joint. Four groups of mice were flared either at day 7, days 7,14 or days 7,14,21. Chronicity increases after every rechallenge.

Figure 8  .

Figure 8  

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Experiments described under figure 7 were performed in the various cytokine-/- mice in the repeated flare protocol (days 7,14,21). Note that arthritis is roughly similar at day 21. The fourth injection of SCW fragments at day 21 caused a major flare, showing still some TNFα dependency, but also note IL1β dependency at that stage (* p< 0.01, compared with relative control strains).

Figure 9  .

Figure 9  

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Histological examination of the knee at day 28 of relapsing SCW arthritis (see figure 8). Safranin O staining shows loss of proteoglycans from the cartilage surface layer in the controls (A) and the TNFα -/- mice (B). In contrast, IL1β -/- mice (C) show major protection against proteoglycan loss, but also display markedly reduced infiltration.

Selected References

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