Various cytokines are involved in the regulation of the immune system and inflammation. Dysregulation of cytokine signaling can cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. This pathway is negatively regulated by suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to JAK or certain cytokine receptors, thereby suppressing further signaling events. Studies using conditional knockout mice have shown that SOCS proteins are key physiological pathological regulators of inflammation as well as immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity, especially helper T cell differentiation.

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Pluripotent stem (iPS) cells are a very promising cell source for models of human genetic diseases and revolutionary new therapies. Successful reprogramming of human blood cells has been reported and is likely to advance the clinical application of iPS cells. In terms of a patient's own somatic cells, generating iPS cells from peripheral blood cells has advantages for clinical applications because these cells are an easily accessible cell source. Of the human peripheral blood cells, T cells can be readily cultured in vitro and proliferate rapidly. Furthermore, only a small amount of peripheral blood is needed to generate iPS cells from T cells, thus increasing the number of patients in whom the technique can be used. iPS cells that contain T-cell receptor (TCR) rearrangements in their genome also have the potential to be traceable markers when establishing novel transplantation therapies. The present review summarizes recent progress in the methods used to generate iPS cells and the future potential of human T cell-derived iPS cells.

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Bone enables locomotive activity, the storage of calcium, and the harboring of the hematopoietic stem cells from which blood and immune cells are derived. Bone is a dynamic organ under the active control of bone cells as well as hematopietic cells and the vascular system. The immune, skeletal and vascular systems share various molecules, including cytokines, signaling molecules, transcription factors and membrane receptors. The dynamic interplay among these systems is observed in a variety of diseases, including rheumatoid arthritis and various cancers in addition to normal development. The framework of the osteo-vascular-immune system has become increasingly important for an independent understanding the biology of each system and will help provide a scientific basis for future therapeutic approaches to diseases related to these systems.

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The bony skeleton enables locomotive activity, the storage of calcium, and the harboring of the hematopoietic stem cells from which blood and immune cells are derived. Although bone appears to be metabolically inert, it is actually a dynamic organ, under the active control of osteoblasts and osteoclasts. Excessive activity of osteoclasts leads to pathological bone resorption, as seen in a variety of local or generalized osteopenic conditions. Therefore, the elucidation of the regulatory mechanisms involved in osteoclastogenesis is critical for the understanding of the skeletal system in both health and disease. The immune and skeletal systems share various molecules, including cytokines, signaling molecules, transcription factors and membrane receptors. Investigation of rheumatoid arthritis (RA), as well as the cloning of RANKL and identification of the various bone phenotypes found in immune-compromised genetically modified mice, have highlighted the importance of the dynamic interplay between the two systems. RANKL stimulates osteoclastogenesis through nuclear factor of activated T cells (NFAT) c1, which is also a crucial regulator of immunity. In RA, bone destruction is caused by the enhanced activity of osteoclasts, which is mainly dependent on interleukin-17-producing helper T cells (T_H17). These findings led to the emergence and subsequent rapid evolution of the field of osteoimmunology. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, and its framework will provide a scientific basis for future therapeutic approaches to diseases related to both of these systems.

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Bone-resorbing osteoclasts develop from monocyte-macrophage lineage cells under the regulation of bone-forming osteoblasts. Osteoblasts express two cytokines essential for osteoclastogenesis, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL, which inhibits the interaction between RANKL and RANK, a receptor of RANKL. Wnt proteins (Wnts) play a central role in the development of organs and tissues. There are two pathways of Wnt signaling. β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. The discovery that loss-of-function mutations in low density lipoprotein receptor-related protein 5 (LRP5), a Wnt co-receptor, led to low bone mass in humans revealed the possible role of Wnt signaling in bone formation: Wnts act on osteoblast precursor cells and promote their differentiation into osteoblasts through the β-catenin-dependent canonical pathway. In addition, Wnts suppress bone resorption by the up-regulation of OPG expression and the down-regulation of RANKL expression in osteoblasts through the same pathway. In contrast, the activation of the β-catenin-independent noncanonical pathway enhances the RANKL-induced osteoclastogenesis. Recent studies have shown that the β-catenin independent noncanonical pathway is also involved in bone resorption induced by arthritis. This review summarizes the regulatory mechanism of bone resorption by Wnt signals.

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T helper 2 (Th2) cells induce allergic inflammation through the production of Th2 cytokines such as IL-4, IL-5, and IL-13. In addition, it has been demonstrated that IL-25 (IL-17E) is a product of activated Th2 cells and initiates and augments Th2-type immune responses. Moreover, recent studies have shown that IL-25 is produced by a number of cell type including, epithelial cells, mast cells, eosinophils, and macrophages. It has also been shown that IL-25 induces Th2-type immune responses through the activation not only of Th2 cells but also of NKT cells and innate cells including MHC IIhigh CD11clow cells, multipotent progenitor cells, natural helper cells, and nuocytes. In vivo, we and others have shown that IL-25 is expressed in the airways in murine asthma models and is involved in the induction of antigen-induced airway inflammation. In human, IL-25 is suggested to be involved in the pathogenesis of asthma and Churg-Strauss syndrome.

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Osteoclasts play critical roles in bone resorption at the site of inflammatory joints, and receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are required for osteoclastogenesis. RANKL, a member of tumor necrosis factor (TNF) family cytokine, is critically involved in the differentiation and fusion of precursors into mature osteoclasts. Binding of RANKL to its receptor RANK activates TNF receptor-associated factor 6 (TRAF6), which is linked to the nuclear factor-κB (NF-κB) and/or mitogen-activated protein kinases (MAPKs). Among these signaling molecules, much attention has been raised to MAPKs as the therapeutic targets for bone resorptive diseases. In this review, we summarized the involvement of MAPKs and the studies using the specific inhibitors of MAPKs in osteoclastogenesis. The inhibitor of tumor progression locus 2 (Tpl2) effectively suppressed osteoclastogenesis, suggesting that the blockade of the particular MAPK pathway could be of clinical importance as the treatment option for bone destructive diseases including rheumatoid arthritis.

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