Peroxisome proliferator-activated receptors (PPARs), are members of the nuclear hormone receptors superfamily of ligand-activated transcriptional factors that include receptors for steroids, thyroid hormone, vitamin D₃ and retinoic acid. PPAR binds to peroxisome proliferator responsive element (PPRE) as a heterodimer with the retinoic receptor (RXR) in the regulation of PPAR target genes. PPARs have been suggested to be important immunomodulatory factors as well as fatty acid regulators. PPARs modulate these activities in different immune cell types such as monocyte/macrophages, lymphocytes, and endothelial cells. PPAR-γ ligands lead to inhibition of the expression of nitric oxide, cytokines, chemokines and adhesion molecules, in part by antagonizing the activities of the transcription factors such as AP-1, and NF-κB. Moreover PPAR-γ ligands including antidiabetic thiazolidinedione and 15-deoxy-Δ^12,14-prostaglandin J₂ have potent tumor modulatory effects against several cancers. PPAR-γ also expressed in chondrocytes, synovial and bone tissues. Activation of the PPAR-γ induced RA synoviocyte apoptosis and suppression of osteoclast differentiatoin in vitro, and ameliorated adjuvant- induced arthritis with suppression of pannus formation and mononuclear cell infiltration in rats. These findings suggest that PPAR-γ ligands may potentially be useful for the treatment of chronic inflammatory diseases including arthritic joint diseases.

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In an air pouch-type carrageenin-induced inflammation model in rats, the selective cyclooxygenase (COX)-2 inhibitor NS-398 dose dependently inhibited the granulation tissue formation, angiogenesis and the level of vascular endothelial growth factor (VEGF) in the granulation tissue. In culture of the minced granulation tissue, PGE₂ induced VEGF production in a concentration-dependent manner. Histamine also induced VEGF production in the granulation tissue in vitro. The H2 receptor antagonist cimetidine, the cAMP antagonist Rp-cAMP and the protein kinase A inhibitor H-89 suppressed the histamine-induced VEGF production in the granulation tissue. However, the H1 receptor antagonist pyrilamine maleate, the H3 receptor antagonist thioperamide, the protein kinase C inhibitors Ro31-8425 and calphostin C or the tyrosine kinase inhibitor genistein showed no effect. Subcutaneous implantation of a cotton thread in the dorsum of histidine decarboxylase-deficient (HDC^-/-) mice, but not in mast cell-deficient (WBB6F₁-W/W^v) mice, induced less angiogenesis with lower levels of VEGF in the granulation tissue than in their corresponding wild-type (HDC^+/+ and WBB6F₁-^+/+) mice. In HDC^-/- mice, the topical injection of histamine or the H2 receptor agonist dimaprit rescued the defective angiogenesis and granulation tissue formation. In addition, cimetidine but not pyrilamine maleate and thioperamide inhibited the histamineinduced angiogenesis in the granulation tissue in HDC^-/- mice. These findings suggest that PGE₂ and histamine play a significant roles in angiogenesis in the inflammatory granulation tissue via induction of VEGF production, and histamine augments VEGF production possibly through the H2 receptor-cAMP-protein kinase A pathway.

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Nitric oxide (NO) plays an important role in various physiological processes. NO is synthesized by a family of NO synthases (NOS). Among the three isoforms of NOS, inducible NOS (iNOS) is closely related to inflammatory and autoimmune diseases. The suppression of excess NO production in participating cells may be helpful in improving disease status. NO inhibitors acting via the new mechanism of dimerization of iNOS are reviewed. The oxygenase domains of two NOS monomers interact to form a dimer, and the NOS isoforms are only active as homodimers. 3-(2,4-difluorophenyl)-6-{2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy}-2-phenylpyridine (PPA250), N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide (Compound 2) and other imidazole derivatives inhibit this step and cause the inhibition of NO production. Crystallographic studies have shown that Compound 2 blocks dimerization through coordinating the heme in the iNOS monomer. PPA250 suppressed the development of arthritis after clinical symptoms had appeared in animal models. PPA250 and Compound 2 also decreased the serum concentration of NO in mice treated with lipopolysaccharide. These results indicate that inhibitors of iNOS homodimerization could be useful therapeutic agents for rheumatoid arthritis, septic shock and other diseases in which NO is involved. In addition, these inhibitors may present new research tools for exploring iNOS dimerization processes.

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Parkinson's disease is a chronic and progressive neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Conventional stereotactic surgery has been performed as surgical therapy and cell grafting into the brain is the newest surgical therapy for that disorder. In order to deliver dopamine or neurotrophic factors into the host striatum, several types of cell lines have been created.
The merits of using cell lines as donors for neural grafting are that they are unlimited as donor source theoretically and they can be genetically modified. However, when using cell lines as donors, immunological rejection and tumor formation should be controlled. To overcome these issues, encapsulated cell grafting technique using semipermeable membrane consisted of polymer has been developed. This technique also has safety because the capsule is retrievable after transplantation. In this mini-review, encapsulated cell grafting research using neurotransmitter and/or neurotrophic factor secreting cell lines will be summarized and future perspectives will be performed from the aspects of therapy for neurological disorders.

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SR-PSOX and CXCL16, which were originally identified as a scavenger receptor and a transmembrane-type chemokine, respectively, are strikingly proved to be essentially identical. Here, we demonstrate that, while soluble SR-PSOX/CXCL16 is chemotactic for CXCR6-expressing cells, membrane-bound SR-PSOX/CXCL16 mediates adhesion and phagocytosis of both Gram-negative and Gram-positive bacteria. Importantly, our prepared anti- SR/PSOX monoclonal antibody, which suppressed chemotactic activity of SR-PSOX, significantly inhibited bacterial phagocytosis by antigen-presenting cells including dendritic cells. Various scavenger receptor ligands inhibited not only scavenger receptor activity but also chemotactic activities of SR-PSOX. In addition, both activities were similarly impaired in a series of mutants in which one basic amino acid in the chemokine domain of SRPSOX was replaced by alanine. Thus, SR-PSOX/CXCL16 was shown to play a role in both innate and adaptive immunity by mediating phagocytosis of bacteria as well as recruitment of CXCR6-expressing T cells by antigenpresenting cells through the same chemokine domain.

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Using chimeric resistant MRL/lpr mice, we have very recently established a novel BMT method, called intrabone marrow (IBM)-BMT. IBM-BMT is far superior to conventional intravenous-BMT (IV-BMT), since it can be used to treat autoimmune diseases in MRL/lpr mice. In addition, we have established a new method for bone marrow cell-harvesting, called Perfusion Method (PM). BMCs collected by the PM contain both pluripotent hemopoietic stem cells and mesenchymal stem cells, but not T cells due to peripheral blood contamination. Therefore, when PM + IBM-BMT are carried out, neither GvHD nor graft reject occurs. This method should therefore become a valuable regeneration therapy for osteoporosis, emphysema, etc.

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Our strategy for tissue regeneration is to induce maximum intrinsic healing potential at the site of a tissue defect, applying the elements of tissue engineering. Regeneration of periodontal tissues occurs through the combined application of a collagen sponge scaffold and gelatin microspheres incorporating basic fibroblast growth factor (bFGF) for controlled release. This “sandwich membrane” with or without bFGF (100μg) was applied to a three-walled alveolar bone defect (3 x 4 x 4 mm) in nine dogs. Periodontal tissues, both hard and soft, treated with bFGF were effectively regenerated four weeks after the operation with functional recovery of the periodontal ligament in parts. Next, the effect of combining cells with the treatment was evaluated. Periodontal fenestration defects (6 x 4 mm) were created bilaterally in the maxillary canines of six dogs. One of these was filled with the collagen sponge scaffold seeded with autologous periodontal ligament-derived cells (3 x 10⁵), and the other was left empty. After four weeks, on the cell-seeded side, regeneration of the cementum was observed uniformly on the root surfaces, indicating that the seeded cells had formed new cementum. Our findings suggest a promising new approach to periodontal regeneration that is based upon in situ tissue engineering.

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