[in Japanese]

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Gut is always exposed to enteric bacteria and food antigens, but maintains its homeostasis without the development of acute or chronic inflammation in normal situations. In contrast, abnormal innate immunity to enteric flora may develop intestinal inflammation in inflammatory bowel disease (IBD). This paper reviewed recent studies regarding intestinal macrophage (Mφ) function in gut. Intestinal Mφ contributes to the elimination of pathogens and gut immune homeostasis. However, it also causes chronic inflammation by producing proinflammatory cytokines. Thus, intestinal Mφ is “a double-edged sword” for individuals. Dysregulation of this mucosal immune system may induce abnormal responses to commensal and food antigen resulting in development of IBD.

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FTY720 (Fingolimod) is the first of a new immunomodulator class: sphingosine 1-phosphate (S1P) receptor modulator. We have found FTY720 by chemical modification of a natural product, myriocin derived from Isaria sinclairii, a kind of vegetative wasp. FTY720 is orally active and is highly effective in various autoimmune disease models including experimental autoimmune encephalomyelitis (EAE), adjuvant- or collagen-induced arthritis, and lupus nephritis. Particularly, oral administration of FTY720 shows marked therapeutic effects on EAE in mice with a significant reduction of demyelination and T cell infiltration in the central nervous system. A most striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating effects. It is revealed that the reduction of circulating lymphocytes by FTY720 is due to sequestration of lymphocytes into secondary lymphoid organs. FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinases. FTY720-P acts as a potent agonist at S1P receptor type 1 (S1P₁), internalizes S1P₁ on lymphocytes, and inhibits migration of lymphocytes toward S1P. It is highly likely that immunomodulating effects of FTY720 are caused by inhibition of S1P/S1P₁-dependent lymphocyte egress from secondary lymphoid organs. Moreover, it is suggested that direct effects of FTY720-P on neural cells via S1P receptors promote neuroprotection. Since FTY720 possesses a novel mechanism of action and is highly effective in relapsing remitting multiple sclerosis patients, it is presumed that oral FTY720 provides a new therapeutic approach for autoimmune diseases including multiple sclerosis.

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The H⁺-ATP synthase has been found in all energy transducing membranes such as mitochondria and chloroplasts, and catalyzes the synthesis of ATP with the energy that derives from electron transfer in the respiratory or photosynthetic electron transport chains. Recent studies, however, have shown that some of its subunits localize in the plasma membrane of neoplastic, endothelial, and hepatic cells. Moreover, it has been proposed that the enzyme may be a receptor for ligands such as angiostatin and apolipoprotein A-1 in endothelial and hepatic cells, respectively. Along the same line, Moser et al. and we showed that cell surface H⁺-ATP synthase is active in ATP synthesis and small molecular substances targeting F1 subunit complex of H⁺-ATP synthase, inhibit proliferation, migration, and tube formation in Matrigel of HUVECs, suggesting that the activity of cell surface H⁺-ATP synthase contributes to regulation of angiogenesis. In addition to these findings, we recently found that the expression of the cell surface H⁺-ATP synthase complex was markedly increased during adipocyte differentiation and that the treatment of differentiated 3T3-L1 adipocytes with H⁺-ATP synthase inhibitors leads to the decrease in the cytosolic lipid droplet accumulation. The present results show that cell surface H⁺-ATP synthase has a previously unsuspected role on lipid metabolism. This paper briefly reviews the recent evidence for a role of cell surface H⁺-ATP synthase on lipid metabolism in adipocytes.

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Mesenchymal support plays crucial roles in both normal and cancer tissue development. In the skin, dermal mesenchymal fibroblasts provide keratinocytes with many cytokines as critical crosstalk molecules through epithelial-mesenchymal interactions. A number of reports have demonstrated that mesenchymal stem cells and myofibroblasts participate in skin repair. Although the importance of both mesenchymal support and the mesenchymal cell phenotype has been recognized, the relationship between the mesenchymal cell phenotype and the paracrine/autocrine action remains unclear. Moreover, the organ that supplies these supportive mesenchymal cell types within the injured tissue is still unclear. In the skin, it is also unknown whether non-skin organ-derived mesenchymal cells, other than the bone marrow and adipose tissue, affect epidermal regeneration through mesenchymal-epithelial interactions. Here, we highlight recent findings regarding the paracrine/autocrine action and phenotypic characters of non-skin-derived mesenchymal cells. We also briefly present our preliminary data regarding the supporting effect of cancer-associated fibroblasts on normal tissue repair.

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In atopic dermatitis (AD), severe itching and scratching not only impacts the patient's quality of life, but also exacerbates the disease; however, the precise underlying mechanisms of itching in AD remain elusive. We have previously reported a special diet-induced, mouse model of AD. This article reviews the characteristics of the model, and the chronological and pharmacological analyses of the pathology. HR-1 hairless mice fed a commercial special diet, HR-AD, but not a normal diet, showed scaly dry red skin resembling AD. To evaluate the degree of itching, spontaneous scratching was analyzed. As a result, scratching with long duration was observed in HR-AD-fed mice, as confirmed by prolongation of duration of one scratching bout. Chronological analysis of the pathologies in HR-AD-fed mice revealed that the prolonged scratching was coincident with the development of skin barrier dysfunction, while skin inflammation with recruitment of inflammatory cells, such as CD4⁺ T cells, eosinophils, and mast cells, and serum IgE elevations apparently followed the prolonged scratching. Epidermal nerve sprouting was detected almost coincidently with the prolonged scratching. Pharmacological analysis of the scratching behavior indicated that the prolonged scratching was suppressed by a μ-opioid receptor antagonist, but not by antihistamine, similar to AD patients. Although treatment with corticosteroid suppressed the skin inflammation, it was not effective against the prolonged scratching, the dry skin symptoms, and the epidermal nerve sprouting. Petrolatum ointment inhibited the prolonged scratching during the amelioration of skin barrier dysfunction. Furthermore, the barrier disrupted-dry skin was alleviated by oral administration of essential fatty acid, linoleic acid (LA), suggesting that LA deficiency appears to be responsible for the symptoms. Taken together, these findings suggest that skin barrier dysfunction is closely associated with the development of AD-like pruritus in this model.

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The novel T helper subset, Th17, plays a critical role in the pathogenesis of a variety of chronic inflammatory disorders such as rheumatoid arthritis, Crohn's disease, and others. Although inflammatory dendritic cells (DCs), such as DCs producing TNFα and iNOS, have been suggested to act as an inducer of Th17-immunity both in humans and mice in vivo; it is unclear how DCs elicit Th17-immunity. Recently, some Th17-differentiation pathways, both TGF-β-dependent and -independent pathways, have been identified in mice. However, the DC biology to evoke Th17-immunity in chronic inflammation or autoimmunity has not yet been clarified, in particular, in human cells. This review summarizes and discusses the induction of Th17 cells by DCs.

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Tumor necrosis factor (TNF)-α is one of the most important factors in HBV infection and HBV infection-related diseases. Although TNF-α is critical and beneficial in HBV clearance, the liver injury is progressed by the up-regulation of TNF-α production. Taken together, TNF-α contribute to the cure and increase of severity in acute hepatitis caused by HBV. It is very important to understand the role of TNF-α, which has two-wedge sword in HBV infection, and the mechanism of TNF-α production. This review briefly overviews up to date about the role of TNF-α in HBV-induced liver injury and HBV clearance, including our results achieved recently.

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Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-mediated disease model for multiple sclerosis (MS). When SJL/J mice are immunized with myelin proteolipid protein (PLP), EAE symptoms were developed within 2 weeks, remitted thereafter, and then relapsed at about 3 weeks after immunization, indicating that EAE induced by PLP in SJL/J mice shares a certain characteristic with relapsing remitting MS. In this study, we evaluated the preventing effect of fingolimod (FTY720), a sphingosine 1-phosphate receptor modulator, on relapse of EAE induced by PLP in SJL/J mice. When FTY720 at oral does of 0.1 and 0.3 mg/kg was administered daily after establishment of EAE, relapse of EAE was markedly inhibited during administration period. The relapse of EAE was significantly inhibited by subcutaneous administration of recombinant mouse interferon-β (rm-IFN-β) at 10000 IU every other day at early period; however EAE was relapsed in the half number of mice in latter period. These results indicate that FTY720 shows a more marked preventing effect on relapse of EAE compared with rm-IFN-β. By immunohistochemical staining, it is revealed that the area of demyelination and the infiltration of CD4 T cells are significantly reduced in the spinal cords of EAE mice by FTY720. Interestingly, FTY720 markedly decreased infiltration of PLP-specific, interleukin 17-expressing CD4 T cells (Th17 cells) into the spinal cords. Consequently, the preventing effect of FTY720 on relapse of EAE is likely due to reduction of infiltration of encephalitogenic CD4 T cells into the central nervous system.

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