Abstract
Interleukin (IL)-35 is an immunosuppressive cytokine mainly produced by regulatory T cells. IL-35 mediates immunological functions by suppressing the inflammatory immune response. However, the role of IL-35 in bone-destructive diseases remains unclear, especially in terms of osteoclastogenesis. Therefore, the current study investigated the synergistic effect of IL-35 on osteoclastogenesis that is involved the pathogeneses of periodontitis and rheumatoid arthritis. Osteoclastic differentiation and osteoclastogenesis of RAW264 (RAW) cells induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) and IL-35 were evaluated by tartrate-resistant acid phosphate staining, hydroxyapatite resorption assays, and quantitative polymerase chain reaction. The effect of IL-35 on RANKL-stimulated signaling pathways was assessed by Western blot analysis. Costimulation of RAW cells by RANKL and IL-35 induced osteoclastogenesis significantly compared with stimulation by RANKL alone. Phosphorylations of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase tended to be increased by RANKL and IL-35 compared with RANKL or IL-35 alone. Additionally, the osteoclastogenesis induced by RANKL and IL-35 was suppressed by inhibition of ERK. In this study, IL-35 and RANKL induced osteoclastogenesis synergistically. Previous reports have shown that IL-35 suppresses the differentiation of osteoclasts. Therefore, IL-35 might play dual roles of destruction and protection in osteoclastogenesis.
Highlights
Bone-destructive diseases, including rheumatoid arthritis, osteoarthritis, osteoporosis, and periodontitis, are caused by inflammation or infection in diseased sites and lead to an imbalance of bone homoeostasis, resulting in severe bone destruction [1,2,3,4]
Osteoclasts and osteoblasts are mainly involved in bone resorption and the receptor activator of nuclear factor (NF)-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) pathway plays a decisive role in the crosstalk between bone-destructive osteoclasts and osteogenic osteoblasts
We stimulated RANKL-treated RAW cells with or without IL-35 to determine whether IL-35 affects RANKL-dependent osteoclastogenesis
Summary
Bone-destructive diseases, including rheumatoid arthritis, osteoarthritis, osteoporosis, and periodontitis, are caused by inflammation or infection in diseased sites and lead to an imbalance of bone homoeostasis, resulting in severe bone destruction [1,2,3,4]. Bone homeostasis is affected by immune cells and cytokines through stimulating osteocytes, osteoblasts, and osteoclasts [5]. IL-35, an immunosuppressive cytokine mainly produced by regulatory T cells (Tregs), mediates immunological functions by suppressing the inflammatory immune response [10]. IL-35 expression is affected by several immune and inflammatory states such as rheumatoid arthritis, inflammatory bowel disease, systemic sclerosis, asthma, chronic obstructive pulmonary disease, and periodontal disease [4,18,19,20,21,22]. Numerous studies related to the expression or function of IL-35 in bone-destructive disease have been reported recently. This study examined the function of IL-35 in osteoclastogenesis using monocytes only and investigated the pathological mechanism of IL-35 for the development of clinical therapies for bone-destructive diseases
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