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The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models.

Lubberts E, Koenders MI, van den Berg WB - Arthritis Res. Ther. (2004)

Bottom Line: Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo.From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process.Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. E.Lubberts@reuma.umcn.nl

ABSTRACT
Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes. High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however, IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-alpha, IL-1, and receptor activator of NF-kappaB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17 has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy.

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Schematic overview of the mechanism of interleukin-17 (IL-17) in bone resorption. The interrelationship of IL-17 with receptor activator of NF-κB ligand (RANKL), IL-1, tumor necrosis factor (TNF) and the modulatory role of IL-4 and osteoprotegerin (OPG) is presented. OC, osteoclast.
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Figure 2: Schematic overview of the mechanism of interleukin-17 (IL-17) in bone resorption. The interrelationship of IL-17 with receptor activator of NF-κB ligand (RANKL), IL-1, tumor necrosis factor (TNF) and the modulatory role of IL-4 and osteoprotegerin (OPG) is presented. OC, osteoclast.

Mentions: In addition to the role of IL-17 in cartilage destruction, this T cell cytokine is a potent stimulator of osteoclastogenesis (Fig. 2). Promotion of type I collagen degradation in synovium and bone by IL-17 has been demonstrated, and when combined with IL-1, a marked synergistic release of collagen was noted [44]. IL-17 in combination with TNF-α increased osteoclastic resorption in vitro [58]. Furthermore, IL-17 induced the expression of RANKL in cultures of osteoblasts [31]. RANKL is a crucial regulator of osteoclastogenesis [59]. RANKL binds to its unique receptor activator of NF-κB (RANK) [60], and the RANKL/ RANK pathway seems of crucial importance in osteoclastogenesis and the bone erosion process. RANKL and the decoy receptor osteoprotegerin [61] are important positive and negative regulators of osteoclastogenesis and bone resorption. Regulation of IL-17 and RANKL, as shown by IL-4 gene therapy in collagen arthritis, prevents osteoclastogenesis and bone erosion [62]. Systemic treatment with a soluble IL-17 receptor fusion protein (sIL-17R:Fc) starting before arthritis expression in experimental arthritis prevented bone erosion [41,63]. Moreover, development of bone erosion in the chronic relapsing streptococcal cell wall-induced arthritis model in IL-17R-deficient mice was significantly suppressed (Lubberts E, Van den Berg WB, Kolls JK, unpublished data). In contrast, local IL-17 overexpression in the knee joint of CII-immunized mice resulted in promotion of collagen arthritis and aggravated joint destruction [43,64]. In the CIA model it was shown that IL-17 promoted bone erosion through loss of the RANKL/osteoprotegerin balance [64]. Systemic treatment with osteoprotegerin prevented joint damage induced by local IL-17 gene transfer in CII-immunized mice. This strongly suggests that IL-17 is a potent inducer of RANKL and that the IL-17-induced promotion of bone erosion is strongly mediated by RANKL.


The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models.

Lubberts E, Koenders MI, van den Berg WB - Arthritis Res. Ther. (2004)

Schematic overview of the mechanism of interleukin-17 (IL-17) in bone resorption. The interrelationship of IL-17 with receptor activator of NF-κB ligand (RANKL), IL-1, tumor necrosis factor (TNF) and the modulatory role of IL-4 and osteoprotegerin (OPG) is presented. OC, osteoclast.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064899&req=5

Figure 2: Schematic overview of the mechanism of interleukin-17 (IL-17) in bone resorption. The interrelationship of IL-17 with receptor activator of NF-κB ligand (RANKL), IL-1, tumor necrosis factor (TNF) and the modulatory role of IL-4 and osteoprotegerin (OPG) is presented. OC, osteoclast.
Mentions: In addition to the role of IL-17 in cartilage destruction, this T cell cytokine is a potent stimulator of osteoclastogenesis (Fig. 2). Promotion of type I collagen degradation in synovium and bone by IL-17 has been demonstrated, and when combined with IL-1, a marked synergistic release of collagen was noted [44]. IL-17 in combination with TNF-α increased osteoclastic resorption in vitro [58]. Furthermore, IL-17 induced the expression of RANKL in cultures of osteoblasts [31]. RANKL is a crucial regulator of osteoclastogenesis [59]. RANKL binds to its unique receptor activator of NF-κB (RANK) [60], and the RANKL/ RANK pathway seems of crucial importance in osteoclastogenesis and the bone erosion process. RANKL and the decoy receptor osteoprotegerin [61] are important positive and negative regulators of osteoclastogenesis and bone resorption. Regulation of IL-17 and RANKL, as shown by IL-4 gene therapy in collagen arthritis, prevents osteoclastogenesis and bone erosion [62]. Systemic treatment with a soluble IL-17 receptor fusion protein (sIL-17R:Fc) starting before arthritis expression in experimental arthritis prevented bone erosion [41,63]. Moreover, development of bone erosion in the chronic relapsing streptococcal cell wall-induced arthritis model in IL-17R-deficient mice was significantly suppressed (Lubberts E, Van den Berg WB, Kolls JK, unpublished data). In contrast, local IL-17 overexpression in the knee joint of CII-immunized mice resulted in promotion of collagen arthritis and aggravated joint destruction [43,64]. In the CIA model it was shown that IL-17 promoted bone erosion through loss of the RANKL/osteoprotegerin balance [64]. Systemic treatment with osteoprotegerin prevented joint damage induced by local IL-17 gene transfer in CII-immunized mice. This strongly suggests that IL-17 is a potent inducer of RANKL and that the IL-17-induced promotion of bone erosion is strongly mediated by RANKL.

Bottom Line: Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo.From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process.Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. E.Lubberts@reuma.umcn.nl

ABSTRACT
Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes. High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however, IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-alpha, IL-1, and receptor activator of NF-kappaB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17 has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy.

Show MeSH
Related in: MedlinePlus