IL-23 Induces Human Osteoclastogenesis via IL-17 In Vitro
IL-23 Induces Human Osteoclastogenesis via IL-17 In Vitro
This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-αlpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.
Rheumatoid arthritis is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone. Our group and another have detected osteoclasts in synovial tissues and eroded bone surfaces, suggesting that osteoclastic bone resorption is involved in the pathogenesis of rheumatoid arthritis (RA).
Furthermore, levels of inflammatory cytokines such as TNF-α, IL-6, and IL-1 are elevated in synovial fluids of patients with RA, and the cytokines promote bone resorption by inducing the differentiation or activation of osteoclasts. It is well known that attenuating the activity of inflammatory cytokines in patients with RA inhibits bone resorption and destruction.
IL-23, which was recently identified as a heterodimeric, proinflammatory cytokine and new member of the IL-12 family, is secreted by antigen-presenting cells. IL-23 is composed of p19 and p40 subunits and shares a common p40 subunit with IL-12. IL-23 signals through the IL-23 receptor complex, which is composed of the IL-12 receptor ß chain and the IL-23 receptor. IL-23 was initially described as a cytokine able to induce the expression of IFN-γ in human CD45RO-positive (memory) T cells and to activate memory T cells to secrete inflammatory cytokines including IFN-γ and IL-17. Furthermore, it is reported that recombinant human (rh)IL-23 upregulates the production of IFN-γ, IL-17, and IL-10 in activated human naïve T cells. In models of T helper type 1 (Th1) differentiation of human T cells, it was initially proposed that IL-23 acts later than IL-12 and maintains Th1 commitment by its preferential action on memory T cells.
In animal studies, it is reported that IL-23-deficient (IL-23 p19-/-) mice are resistant to experimental autoimmune encephalomyelitis (EAE), whereas IL-12 (p35)-deficient mice are still susceptible to inflammation. Murphy and colleagues reported that mice with collagen-induced arthritis (CIA) and IL-23 deficiency (IL-23 p19-/-) are completely resistant to the development of joint and bone pathology and that IL-23 is required for the induction of joint inflammatory mediators including IL-17 and TNF-α. Furthermore, transgenic mice constitutively overexpressing IL-23 p19 develop spontaneous severe multi-organ inflammation with elevated levels of TNF-α. These findings suggest that IL-23 has a pivotal role in the establishment and maintenance of inflammatory autoimmune diseases. In addition, some reports have established the idea of a critical function for the IL-23IL-17 pathway in some autoimmune diseases and emphasize the importance of understanding the origins of development of IL-17 effector cells.
IL-17 is a proinflammatory cytokine secreted by activated T cells or neutrophils. We have reported that IL-17 levels in synovial fluids are significantly higher in patients with RA than in patients with osteoarthritis and that IL-17 stimulates osteoclast differentiation by inducing the expression of receptor activator of NF-κB ligand (RANKL) via a mechanism involving the synthesis of prostaglandin E2 in osteoblasts in vitro. In addition, we reported that IL-17 directly stimulates human osteoclastogenesis from human monocytes alone, via the TNF-α or RANKRANKL pathway. Recently, some groups have reported that IL-17 is also important in joint destruction in animal models and in patients with RA. It is therefore indicated that IL-23 is involved in osteoclastic bone resorption, at least in part via the IL-17 pathway, and that IL-23 is important in the progression of arthritis. However, the direct effect of IL-23 on human osteoclastogenesis from peripheral blood mononuclear cells (PBMC) and the role of anti-IL-23 antibody in CIA in rats remain unclear.
In the present study we examined the direct role of IL-23 in osteoclastogenesis by using cultures of human PBMC. Furthermore, to clarify the role of IL-23 antibody in the later stage of CIA, rats with CIA were treated with anti-IL-23 antibody at a later stage after the onset of clinical arthritis.
This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-αlpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.
Rheumatoid arthritis is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone. Our group and another have detected osteoclasts in synovial tissues and eroded bone surfaces, suggesting that osteoclastic bone resorption is involved in the pathogenesis of rheumatoid arthritis (RA).
Furthermore, levels of inflammatory cytokines such as TNF-α, IL-6, and IL-1 are elevated in synovial fluids of patients with RA, and the cytokines promote bone resorption by inducing the differentiation or activation of osteoclasts. It is well known that attenuating the activity of inflammatory cytokines in patients with RA inhibits bone resorption and destruction.
IL-23, which was recently identified as a heterodimeric, proinflammatory cytokine and new member of the IL-12 family, is secreted by antigen-presenting cells. IL-23 is composed of p19 and p40 subunits and shares a common p40 subunit with IL-12. IL-23 signals through the IL-23 receptor complex, which is composed of the IL-12 receptor ß chain and the IL-23 receptor. IL-23 was initially described as a cytokine able to induce the expression of IFN-γ in human CD45RO-positive (memory) T cells and to activate memory T cells to secrete inflammatory cytokines including IFN-γ and IL-17. Furthermore, it is reported that recombinant human (rh)IL-23 upregulates the production of IFN-γ, IL-17, and IL-10 in activated human naïve T cells. In models of T helper type 1 (Th1) differentiation of human T cells, it was initially proposed that IL-23 acts later than IL-12 and maintains Th1 commitment by its preferential action on memory T cells.
In animal studies, it is reported that IL-23-deficient (IL-23 p19-/-) mice are resistant to experimental autoimmune encephalomyelitis (EAE), whereas IL-12 (p35)-deficient mice are still susceptible to inflammation. Murphy and colleagues reported that mice with collagen-induced arthritis (CIA) and IL-23 deficiency (IL-23 p19-/-) are completely resistant to the development of joint and bone pathology and that IL-23 is required for the induction of joint inflammatory mediators including IL-17 and TNF-α. Furthermore, transgenic mice constitutively overexpressing IL-23 p19 develop spontaneous severe multi-organ inflammation with elevated levels of TNF-α. These findings suggest that IL-23 has a pivotal role in the establishment and maintenance of inflammatory autoimmune diseases. In addition, some reports have established the idea of a critical function for the IL-23IL-17 pathway in some autoimmune diseases and emphasize the importance of understanding the origins of development of IL-17 effector cells.
IL-17 is a proinflammatory cytokine secreted by activated T cells or neutrophils. We have reported that IL-17 levels in synovial fluids are significantly higher in patients with RA than in patients with osteoarthritis and that IL-17 stimulates osteoclast differentiation by inducing the expression of receptor activator of NF-κB ligand (RANKL) via a mechanism involving the synthesis of prostaglandin E2 in osteoblasts in vitro. In addition, we reported that IL-17 directly stimulates human osteoclastogenesis from human monocytes alone, via the TNF-α or RANKRANKL pathway. Recently, some groups have reported that IL-17 is also important in joint destruction in animal models and in patients with RA. It is therefore indicated that IL-23 is involved in osteoclastic bone resorption, at least in part via the IL-17 pathway, and that IL-23 is important in the progression of arthritis. However, the direct effect of IL-23 on human osteoclastogenesis from peripheral blood mononuclear cells (PBMC) and the role of anti-IL-23 antibody in CIA in rats remain unclear.
In the present study we examined the direct role of IL-23 in osteoclastogenesis by using cultures of human PBMC. Furthermore, to clarify the role of IL-23 antibody in the later stage of CIA, rats with CIA were treated with anti-IL-23 antibody at a later stage after the onset of clinical arthritis.
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