TNF-induced structural joint damage is mediated by IL-1

Abstract

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA. We removed the effects of IL-1 from a TNF-mediated inflammatory joint disease by crossing IL-1␣ and ␤-deficient mice (IL-1 ؊/؊ ) with arthritic human TNF-transgenic (hTNFtg) mice. Development of synovial inflammation was almost unaffected on IL-1 deficiency, but bone erosion and osteoclast formation were significantly reduced in IL-1 ؊/؊ hTNFtg mice, compared with hTNFtg mice based on an intrinsic differentiation defect of IL-1-deficient monocytes. Most dramatically, however, cartilage damage was absent in IL-1 ؊/؊ hTNFtg mice. Chimera studies revealed that protection of cartilage is based on the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading to decreased expression of ADAMTS-5 and MMP-3. These data show that TNF-mediated cartilage damage is completely and TNF-mediated bone damage is partially dependent on IL-1, suggesting that IL-1 is a crucial mediator for inflammatory cartilage and bone degradation.cytokines ͉ rheumatoid arthritis ͉ cartilage

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

“…Of particular interest in this context is the fact that IL-1␣ A final important issue is how the distinct inflammatory milieu in the inflamed SpA joint translates into differences in phenotype and disease progression as compared with that in the inflamed RA joint. In RA, TNF␣ and IL-1␤ are important drivers of bone and cartilage damage (46)(47)(48)(49)(50). Although lower levels of these cytokines in the inflamed SpA joint may contribute to the preservation of tissue integrity, no clear differences in downstream destructive processes have yet been demonstrated between SpA and RA (34,46,51).…”

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

“…In addition, inflammatory cytokines produced by monocytes and resident mesenchymal cells are of key importance for osteoclast formation, as they regulate expression of RANKL and also sensitize monocytes for osteoclast differentiation. In this context, TNF-a, and IL-1 are of particular key importance for osteoclast formation and bone resorption in inflammatory tissue [5,6].Aside from classical pro-inflammatory mediators like TNF-a and IL-1, which are preferentially linked to cells of the innate immune system, adaptive immunity, particularly T cells, link immune activation to bone loss [7]. Activated T cells express RANKL and among the various T-cell lineages Th17 cells appear to have consistent pro-osteoclastogenic properties [8].…”

“…IL-12 inhibition did yield very similar effects, albeit rescue of bone protection did not achieve (Fig. 5B), suggesting that upregulation of anti-osteoclastogenic IL-4 and IL-12 are of key importance in mediating the bone protective effect of IL-17 neutralization.Blockade of IL-17A in the absence of IL-1 abrogates TNF-mediated arthritis and bone destructionAs IL-1 is an important downstream mediator of TNF-induced bone destruction [6,16] and is also involved in the differentiation of Th17 cells [17], we were interested to test the influence of IL-1, when blocking IL-17A in TNF-a-mediated arthritis. We therefore blocked IL-17 in IL-1 À/À hTNFtg mice, which developed inflammatory arthritis but showed less bone destruction.…”

“…TNF-a also induces the expression of IL-1, which has been identified as an important mediator for osteoclast formation. In particular, IL-1 stimulates RANKL expression as well as RANK expression rendering monocytes more susceptible to osteoclastogenesis [6,16]. Aside IL-1, T-cell-derived lymphokines have been elegantly documented to be instrumental in regulating osteoclast differentiation.…”

“…As IL-1 is an important downstream mediator of TNF-induced bone destruction [6,16] and is also involved in the differentiation of Th17 cells [17], we were interested to test the influence of IL-1, when blocking IL-17A in TNF-a-mediated arthritis. We therefore blocked IL-17 in IL-1 À/À hTNFtg mice, which developed inflammatory arthritis but showed less bone destruction.…”