IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

Abstract

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 NFkappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha 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.

Th17 Cells, Not IL-17+ γδ T Cells, Drive Arthritic Bone Destruction in Mice and Humans

“…In a pathogenic setting, IL-23 is known to enhance the effector functions of Th17 cells (19,20,50,51), as well as IL-23R + gd T cells (18,22,52). Our data are in line with studies by Yago et al, who demonstrated that IL-23 stimulates human osteoclast differentiation indirectly via Th17 cell activation (53). We demonstrated that the osteoclastogenic potential of T cells from the periphery was enhanced when cells were either precultured with IL-23 or derived from IL-23-rich arthritic joints.…”

IL‐23 promotes osteoclast formation by up‐regulation of receptor activator of NF‐κB (RANK) expression in myeloid precursor cells

“…However, IL-23 alone did not induce osteoclast formation. A previous study suggested that IL-23 was capable of inducing osteoclast formation in the absence of RANKL [49]. However, as enriched rather than pure cell populations were used, a contribution from other sources such as T cells could not be excluded.…”

Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A4 to promote the resolution of allergic airway inflammation

“…IL-23 is involved in the pathobiology of numerous chronic diseases, including colitis, encephalitis, psoriasis, rheumatoid arthritis and cancer 12,14,15,34 , and is critical for the survival of T H -17 cells 12,30 . These T cells release IL-17A, a cytokine that increases production of several proinflammatory molecules, including IL-1 and TNF 35 .…”