The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. NLRP3 inflammasome activation and IL-1β secretion have recently emerged as a central mechanism in the pathogenesis of disease. Here we describe four genetically defined syndromes like cryopyrin-associated periodic syndromes (CAPS, cryopyrinopathies), mevalonate kinase deficiency (MKD) or hyper-IgD and periodic fever syndrome (HIDS), pyogenic aseptic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome), and deficiency of interleukin-1-receptor antagonist (DIRA) along with the pitfall for understanding the pathphysiology.

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In general, the body tissue is composed of cells and their local environment. The environment plays an essential role in the attachment, proliferation, migration or differentiation of cells and the subsequent their 3-dimensional organization, which are important biological functions of cells to be investigated for cell-based tissue regeneration. The cell behavior is influenced by the surface and bulk properties of substrates for cell culture, such as the surface hydrophobicity, charge or morphology and the material stiffness. The proliferation and differentiation of cells can be biologically changed by the surface hydrophobicity and charge of culture substrates. The stiffness of culture substrates also modifies the differentiation profiles of stem cells. The combination of culture substrates with bioactive molecules promotes the proliferation and differentiation of stem cells. Various 3-demensional substrates are designed to demonstrate the effect of the mechanical and biological properties on the proliferation and differentiation of cells. Artificial manipulation of cell functions has been experimentally tried. Genetic engineering with transfection technology of plasmid DNA and small interference RNA (siRNA) enabled cells to activate their biological functions and modify their differentiation direction. This paper overviews basic researches on the interaction between cells and cultures substrates with different physicochemical properties. Several cell researches with different culture substrates are introduced to emphasize significance of biomaterial technology in the basic research of stem cells.

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Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue- specific alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is widely distributed in the central and peripheral neuronal systems and exhibits numerous biological activities in mammals. Recently, it was clarified that endogenous CGRP released from primary afferent neurons facilitates the neovascularization indispensable to tumor growth. Angiogenesis in surgical sponge models that mimics tumor stromal reaction was inhibited by a CGRP antagonist, CGRP8-37. The unilateral sciatic nerves (L_1-5) of mice were cut, and Lewis lung carcinoma (LLC) cells were implanted into the subcutaneous tissues of the legs. Tumor growth was significantly reduced in the sites of denervation of these mice, compared with the sham-operated mice. In CGRP knockout mice, the tumor growth and tumor-associated angiogenesis of implanted LLC cells were significantly reduced compared with those in wild-type mice. In LLC-bearing wild-type mice, CGRP precursor mRNA levels in the dorsal root ganglion were increased compared with those in non-LLC bearing mice. This increase was abolished by denervation. In a co-culture system using human umbilical vein endothelial cells (HUVEC) and fibroblasts, CGRP increased tube formation by endothelial cells. VEGF expression was up-regulated in the tumor implantation models in a CGRP-dependent manner. These recent results suggest that sensory nerves facilitate tumor-associated angiogenesis and tumor growth during tumor development via a release of CGRP. The same was true in the processes of wound healing and gastric ulcer healing. Further, CGRP was also reported to enhance the angiogenesis in hind-limb ischemia model. These recent results indicate CGRP may become a novel therapeutic target for controlling angiogenesis.

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Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation and polyarthritis. Inflammatory mediators activate fibroblast-like synovial cells which exhibit very unique characteristics in the process of bone resorption. The rheumatoid synoviocytes produce high levels of prostaglandin E₂ (PGE₂) production through increased cyclooxygenase (COX)-2 expression. PGE₂ is thought to be a major PG species working in RA pathogenesis and PGE₂ exhibits various biological actions: for example, PGE₂ mediates some inflammatory responses and bone resorption as well as activation of osteoclasts. Prostaglandin E synthase (PGES) is an enzyme that acts downstream of COX-2 and catalyzes the final step of PGE₂ biosynthesis. Microsomal PGES (mPGES)-1 shows the coordinated induction with COX-2 under inflammatory conditions. Sphigosine-1-phosphate (S1P) is the final metabolite of the sphingolipid pathway and controls a wide variety of essential cellular processes. S1P is involved in various pathologic conditions and has been implicated as an important mediator in angiogenesis, cancer, and autoimmune diseases such as RA. S1P1 receptor is strongly expressed in RA synovium, and S1P enhances inflammatory cytokine-induced COX-2 expression and PGE₂ production. FTY720 (fingolimod) is a high-affinity agonist for S1P receptors and induces internalization of the receptors. FTY720 has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases such as multiple sclerosis and RA. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. PPARγ is activated by a range of synthetic and naturally occurring substances, including anti-diabetic thiazolidinediones such as troglitazone and 15-deoxy-Δ^12-14-PGJ₂ (15d-PGJ₂). PPARγ ligands suppress arthritis in Lewis rats with adjuvant- induced arthritis, and induce rheumatoid synoviocye apoptosis. This mini-review focuses on the role of lipid mediators in the pathogenesis of RA.

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Rheumatoid arthritis (RA) is a chronic autoimmune disease which primarily affects the synovial joints leading to inflammation, pain and joint deformities. Nonsteroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids, both of which inhibit cyclooxygenase (COX), have been extensively used for treating RA patients. Prostaglandin E synthase (PGES) is a specific biosynthetic enzyme that acts downstream of COX and converts prostaglandin (PG) H₂ to PGE₂. Among PGES isozymes, microsomal PGES-1 (mPGES-1) has been shown to be induced in a variety of cells and tissues under inflammatory conditions. The induction of mPGES-1 in the synovial tissue of RA patients is closely associated with the activation of the tissue by proinflammatory cytokines. Although selective mPGES-1 inhibitors have not yet been widely available, mice lacking mPGES-1 (mPGES-1^-/- mice) have been generated to evaluate the physiological and pathological roles of mPGES-1 in vivo. Recent studies utilizing mPGES-1^-/- mice have demonstrated the significance of mPGES-1 in the process of chronic inflammation and evocation of humoral immune response in autoimmune arthritis models. These recent findings highlight mPGES-1 as a novel therapeutic target for the treatment of autoimmune inflammatory diseases, including RA. Currently, both natural and synthetic chemicals are being tested for inhibition of mPGES-1 activity to produce PGE₂. The present review focuses on the recent advances in understanding the role of mPGES-1 in the pathophysiology of RA.

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FTY720 (Fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs. Oral administration of FTY720 shows a superior efficacy compared to interferon (IFN)-β in relapsing remitting multiple sclerosis (MS), the most common inflammatory disorder of the central nervous system (CNS) and in experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for MS. FTY720 is a structural analogue of sphingosine and is rapidly converted to the (S)-enantiomer of FTY720-phosphate [ (S)-FTY720-P)] by sphingosine kinases. (S)-FTY720-P binds 4 types of S1P receptors (S1P₁, S1P₃, S1P₄, and S1P₅), induces internalization and degradation of lymphocytic S1P₁, and inhibits S1P responsiveness of lymphocytes. Consequently, (S)-FTY720-P acts as a functional antagonist at S1P1 thereby inhibiting S1P-S1P₁ axis-mediated lymphocyte egress from secondary lymphoid organs. Based on this mechanism, FTY720 sequesters myelin antigen-specific CD4 T cells including interleukin 17-expressing helper T cells (Th17 cells) and IFN-γ-expressing type 1 helper T cells (Th1 cells) into the lymph nodes, and reduces the infiltration of these Th cells into the CNS in mouse EAE. Since FTY720 was approved by the United States Food and Drug Administration in September 2010 as a first-line treatment for relapsing remitting MS, it is presumed that oral FTY720 provides a new therapeutic approach for MS.

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Sphingosine 1-phosphate (S1P) acts as an extracellular mediator by binding to G protein- coupled receptors, regulating cell proliferation, angiogenesis and inflammation. FTY720 (FTY) is a high-affinity agonist for S1P receptors, inducing internalization of receptors, rendering the cells unresponsive to S1P. Here, we review the role of S1P signaling for the pathogenesis of autoimmune diseases and the therapeutic effects of FTY on autoimmune diseases.

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Exposure to several chemical compounds in the environment might worsen allergies. However, it remains unclear which chemicals except for contact-sensitizing compounds modify inflammatory and immune responses and how. Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine produced mainly by epithelial cells, plays important roles in the initiation of allergic inflammation. We found that the painting of xylene on ear lobes induced production of TSLP and exacerbated the picryl chloride-induced allergic dermatitis. Thus, there are chemical compounds in the environment which do not have contact-sensitizing activity but cause the production of TSLP and on exacerbation of allergic dermatitis.

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Hematopoietic prostaglandin (PG) D synthase (H-PGDS) is known as key enzyme in the production of PGD₂ and its J series metabolite, 15-deoxy-Δ^{12, 14}-PGJ₂ (15d-PGJ₂), is thought to play an important role for anti-inflammatory effects. Anti-tumor effects of 15d-PGJ₂ has been shown to be involved in both peroxisome proliferator-activated receptor (PPAR) γ independent and dependent pathways. The independent pathway includes the repression of the telomerase reverse transcriptase (TERT) and cyclooxygenase (COX)-2 via the down-regulation of NFκB. The dependent pathway included repression of the vascular endothelial growth factor (VEGF) receptors and COX-2 with down-regulation of NFκB, followed by the activation of PPAR γ. In this review, we focused on the role of 15d-PGJ₂ in anti-tumor effects including our evaluation in mouse bladder carcinoma model.

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Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are members of the innate immune system that recognize pathogens in the cytosol. We have previously revealed that multiple genetic variants of NOD1 and NOD2, components of NLRs, are associated with susceptibility to several granulomatous diseases. Notably, NOD2 loss-of-function and gain-of-function mutations showed susceptibility to Crohn's disease and Blau syndrome, respectively. Furthermore, we have revealed that impaired recognition of intracellular Propionibacterium acnes resulting from a polymorphism in the NOD1 gene is involved in the increased susceptibility of Sarcoidosis in a Japanese population. In this review, we examine the function of NOD1 and NOD2 in innate immunity, with a focus on their differing roles in disease pathogenesis between Japanese and Caucasian populations.

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The concept of bone tissue engineering, which began in the early 1980s, has seen tremendous growth in the numbers of research studies. One of the key areas of research has been in the field of implant surgery, where the challenge is to produce the perfect tissue-engineered bone construct. This practical review summarizes applied state-of-the-art research in the important translational research that has already been initiated in Nagoya University Hospital. The topics that will be covered include, clinical applications in alveolar regeneration for dental implant, tumors surgery and distraction osteogenesis. Although significant challenges remain, there exists an exceptional opportunity to translate basic research in tissue engineering technologies into viable clinical treatments for bone regeneration in implant surgery.

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Outgrowth endothelial progenitor cells (OECs) are expected to be a valuable source of blood vessels for regenerative medicine. Their properties and functions have been intensively studied, but the feasibility of reliable acquisition remains unclear. The aim of this study was to determine an optimized method for obtaining OECs from human umbilical cord blood (hUCB). We isolated mononuclear cells from hUCB and determined the OEC colony formation rate (OEC-CFR) under various conditions on the basis of the following 4 points: 1, cell density; 2, pre-selection of CD45^(-) cells; 3, culture medium; and 4, influence of cryopreservation. The OEC-CFR from CD45^(-) cells was 0.250 colony/5 × 10⁷ ,cells and was dependent on the initial cell density, while the OEC-CFR from total mononuclear cells was 0.347 colony/5 × 10⁷ cells. This result suggested that pre-selection of CD45^(-) cells was not necessary to obtain OECs. Supplementation of the culture medium with microvascular endothelial growth medium (EGM-2-MV) caused an increase in the OEC-CFR. Furthermore, we obtained at least 1 colony from each sample of total mononuclear cells after cryopreservation, although the OEC-CFR was lower than that from fresh cells. Flow cytometric analysis and immunocytochemistry showed that isolated OECs expressed CD31, CD34, CD73, CD146, CD144 and CD309. By confocal microscopy, we confirmed the formation of tubes by OECs on Matrigel. In this study, we proposed an optimized method for the isolation of OECs. This method could be useful for the clinical application of OECs.

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