interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-α) are thought to share several biological actions in experimental models; for example, IL-1 and TNF-α both upregulate the production of inflammatory mediators such as cyclooxygenase type 2 (COX-2), prostaglandin-E2 (PGE2), and nitric oxide.1,2 Experimental studies in human peripheral blood, along with animal model systems, have shown that TNF-α induces IL-1, IL-1 induces TNF-α and IL-1 also further induces IL-1.2-5 Despite the apparent overlapping actions of these cytokines, results from animal models suggest that they may have different and distinct effects.1 For example, considerable increases in TNF-independent production of IL-1 have been observed in a model of streptococcal cell wall (SCW)-induced murine arthritis.6 Regardless of treatment with anti-TNF in this model, erosions developed in these animals, and to a high degree in TNF-deficient mice.6,7 Thus, rheumatoid arthritis (RA) develops even in the complete absence of TNF, whereas IL-1 knockout mice do not develop arthritis.6,7 When the effect of anti-TNF on IL-1 production was investigated in a clinical study using anti-TNF neutralising antibodies, no significant reductions in circulating IL-1 were observed compared with placebo.8
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IL-1 production occurs independently of TNF
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IL-1 has a pivotal role in the pathophysiology of RA, and acts on a range of cell types in the joint space to amplify and perpetuate the RA disease process.9-11 In particular, IL-1 is a potent stimulator of synoviocytes, chondrocytes and osteoblasts (Figure 1).1 Cellular activation by IL-1 occurs through its binding to the membrane-bound IL-1 receptor type I (IL-1RI). The IL-1/IL-1RI complex then forms a heterotrimeric complex with the IL-1 receptor accessory protein (IL-1RAcP), leading to cell signalling and activation.1,3
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IL-1 is a key mediator of synovial inflammation and pannus formation
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Figure 1 IL-1 is a pivotal cytokine involved in the pathophysiology of RA1,28,30,31
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IL-1 is a proinflammatory cytokine that amplifies and perpetuates the disease process in RA.1,28,30,31 |
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In RA, there are increased amounts of IL-1 in the synovium.22,32 |
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In RA patients, IL-1 plasma levels correlate with disease activity.22,32 |
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RA patients with erosive disease have higher synovial and circulating levels of IL-1 than patients without erosions.32 |
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Inflammatory Effects of IL-1
Inflammation is largely responsible for the signs and symptoms of RA (Figure 2). Initially, IL-1 mediates inflammation by recruitment of neutrophils into the joint, activation of macrophages, and stimulation of T- and B-cell proliferation and differentiation.1 On exposure to IL-1, synoviocytes proliferate and produce interleukin-6 (IL-6), prostaglandins (eg, PGE2), and matrix metalloproteases (MMPs; eg, collagenase and stromelysin).1,12
Figure 2 IL-1 plays a key role in many mechanisms of the RA disease process1,28,30
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IL-1 upregulates the production of prostaglandins and other proinflammatory mediators,1,28,30 and thereby accounts for pain, swelling and tenderness typically seen in rheumatoid joint inflammation. |
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IL-1 is a key mediator of synovial inflammation and pannus formation.1,28,30 |
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IL-1 is a pivotal cytokine mediating destruction of bone and cartilage in RA, and also is believed to impair bone and cartilage repair.1,28,30 |
IL-1 in Cartilage and Bone Destruction
RA leads to severe rheumatoid joint destruction and can have profound effects in the long term, causing severe disability through loss of patient functionality. IL-1 plays a key role in cartilage and bone destruction leading to severe joint destruction (Figure 2).
The production of MMPs from IL-1-activated synoviocytes causes proteoglycan degradation, which in turn drives cartilage destruction. The MMP, stromelysin, appears to be pivotal in the activation of collagenase, an enzyme required for cartilage breakdown. The effect of IL-1 on chondrocytes is to inhibit proteoglycan synthesis and stimulate collagen breakdown,13,14 preventing the normal maintenance of cartilage. In experimental models, this loss of cartilage proteoglycans has been shown to occur early in the disease process.15 Additionally, erosion of the cartilage surface is mediated by the formation of pannus and increased migration of polymorphonuclear cells into the synovial tissue; IL-1 has an important role in driving these processes. IL-1 also causes increased production of inducible nitric oxide synthase and consequently nitric oxide as part of the inflammatory process. High levels of nitric oxide kill chondrocytes, the cells responsible for cartilage remodelling.16
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IL-1 is a pivotal cytokine that mediates the destruction of bone and cartilage in RA
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The effects of IL-1 on bone resorption are mediated indirectly through the interaction between osteoprotegerin (OPG) and osteoprotegerin ligand (OPG-L, also known as RANKL), and their effects on osteoclasts—large, multinucleated cells involved in the resorption and removal of bone. OPG is a soluble factor that binds to OPG-L, thereby inhibiting osteoclast maturation and activation, and thus decreasing osteoclastic bone resorption. The balance between OPG-L and OPG determines the relative degree of bone erosion that occurs in a joint. IL-1 acts directly on T cells and osteoblasts to increase expression of OPG-L. OPG-L then stimulates the differentiation of osteoclast precursors to mature osteoclasts. In addition, OPG-L acts directly on mature osteoclasts to increase their resorptive activity.17,18 PGE2 and IL-6 also contribute to osteoclast activity.4,17,19 IL-1 has also been shown to induce osteoblast apoptosis and may thereby prevent new bone formation, which is particularly important when repair is required.20,21
IL-1 in the Prevention of Tissue Repair
IL-1 also impairs the repair process by preventing the formation of the cartilage matrix and by inhibition of proteoglycan synthesis (Figure 2).22-24 TNF-α may be present during these events, but is less potent than IL-1.25,26 In vivo studies involving direct injections of IL-1 and TNF-α into the knee joints of mice have shown that IL-1 is 100 times more potent than TNF-α in inhibiting proteoglycan synthesis.25
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IL-1 is 100 times more potent than TNF-α in inhibiting proteoglycan synthesis
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Involvement of IL-1 in the Pain Mechanism
Patients with RA inevitably experience pain alongside the swelling and tenderness with rheumatoid joint inflammation.27 IL-1 (and TNF-α) strongly induce the production of PGE2, leukotrienes and platelet-activating factor, which are involved in the pain mechanism (Figure 2).28
Evidence that IL-1 has a pivotal role in the pathophysiology and clinical manifestations of RA supports the relevance of IL-1 as a therapeutic target.3,6,28,29
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