昭和55年に炎症研究会から日本炎症学会として正式に学会となった本会は，平成13年には現在の日本炎症・再生医学会と名称変更し，炎症学から再生医学の広い領域を扱うことになった．その間，2度の大会の事務局長をさせていただき，私にとって本学会は非常に重要な学会として位置づけてられている．本学会の最も大きな変化は，本学会が21世紀の先端医療としての再生医学に注目し，再生医学を取り込んだことと認識している．しかし，炎症学と再生医学の学際的融合が十分になされたと感じていない会員もいるのではないかと推測する．その意味から，今後とも，炎症学・再生医学の融合への努力が必要だと感じている．私自身，研究のスタートは炎症とプロスタグランディンで，現在のメインテーマは再生医療であるが，自分の研究を振り返るに，炎症と再生が融合しているとは必ずしも思っていない．しかし，当然のことであるが，炎症の第3期は修復期で，炎症刺激が無くなることによる損傷部位の再生が起こることより，炎症と再生は常に合わせて考える必要がある．

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Lymphopenia results in homeostatic peripheral expansion of lymphocytes in order to maintain T-cell homeostasis. T-cell homeostasis requires the regulation of lymphocytes numbers, function, and diversity responsive to foreign antigen and the maintenance of self-tolerance during lymphopenia-induced proliferation. Accumulating data elucidate that regulatory T cells critically contribute to the control of T cell homeostasis. Moreover, recent studies show that regulatory T cell homeostasis requires the co-existence with conventional T cells which can produce IL-2. Thus, T-cell homeostasis is maintained by the close interactions between regulatory T cells and conventional T cells. Understanding the mechanisms of homeostatic proliferation will lead to new therapeutic interventions for autoimmune diseases.

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Stable cell-cycle arrest is known as “cellular senescence” and is triggered by various stresses. Senescent cells show a series of alterations, including a flat and enlarged morphology, increased in non-specific acidic β-galactosidase activity, chromatin condensation, and changes in gene expression patterns. The onset and maintenance of senescence are regulated by two tumor suppressor proteins, p53 and Rb. The expression of p53 and Rb is regulated by two distinct proteins, Arf and p16^Ink4a, respectively, which are encoded by cdkn2a. Jun dimerization protein (JDP2) is a histone chaperone, which has activities in the inhibition of histone acetyltransferase and in nucleosome assembly/disassembly. Therefore, JDP2 plays key roles in cell growth, cell differentiation, and senescence by regulating the expression of genes. JDP2 inhibits the recruitment of polycomb repressive complexes (PRC-1 and PRC-2) to the promoter of the gene encoding p16^Ink4a and inhibits the methylation of lysine 27 of histone H3 (H3K27). In fact, the PRCs associate with the p16^Ink4a/Arf locus in young proliferating cells and dissociate from it in aged senescent cells. Therefore, it seems that chromatinremodeling factors that regulate the association and dissociation of PRC and are controlled by JDP2 might be important players in the senescence program. The molecular mechanisms that underline the action of JDP2 in cellular aging and replicative senescence by mediating the dissociation of PRCs from the p16^Ink4a/Arf locus are discussed.

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Tumor-associated macrophages (TAMs) of M2 phenotype promote tumor proliferation and relate to poor prognosis in patients with gliobrastoma. We screened natural compounds possessing inhibitory effect on M2 polarization in human monocyte-derived macrophages. Among 130 purified natural compounds, some natural compounds such as glycyrrhizin, medicarpin and solasodine significantly inhibited the expression of CD163, one of the phenotypic markers of M2 macrophages, as well as suppressed the secretion of IL-10, one of the anti-inflammatory cytokine preferentially produced by M2 macrophages, thus suggesting that glycyrrhizin, medicarpin and solasodine suppress macrophage polarization towards M2 phenotype. Therefore, glycyrrhizin, medicarpin and solasodine may be potentially useful new strategy for the prevention and therapy of tumor.

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Although it has been suggested that kinins and tachykinins may be involved in the pathogenesis of allergic rhinitis, inhibitors of these mediators have not yet to be developed for use as therapeutic drugs. Therefore, this study examined whether kinins and tachykinins are involved in the induction of nasal symptoms in a guinea pig pollinosis model.
Sensitized guinea pigs were challenged by forced inhalation of pollen once a week. Sneezing and nasal blockage were observed after pollen challenges. Nasal hyperresponsiveness to an intranasal application of leukotriene (LT) D4 was assessed 2 days after an antigen challenge.
Neither bradykinin receptor (B₁ and B₂) antagonists nor tachykinin receptor (NK₁ and NK₂) antagonists inhibited sneezing and nasal blockage. In contrast, these antagonists significantly suppressed the development of nasal hyperresponsiveness. An especially strong inhibition was noted for the B₂ receptor and the NK₂ receptor antagonists. Furthermore, exogenous intranasal instillation of kinins (bradykinin and des-Arg¹⁰-kallidin) and tachykinins (neurokinin A and substance P) produced nasal hyperresponsiveness that was similar to the antigen-antibody reaction. On the other hand, immediately after a pollen challenge, an increase was noted in the amount of bradykinin in the nasal cavity lavage fluid, followed by elevation of tachykinin levels.
These results indicate that kinins and tachykinins mediate the development of nasal hyperresponsiveness by preferentially activating B₂ and NK₂ receptors. Therefore, these receptor antagonists may prove effective in the treatment of allergic rhinitis.

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Megakaryopoiesis is associated with inflammation, and certain inflammatory cytokines stimulate hematopoietic progenitors to differentiate into megakaryocytes. Interferon-γ ( IFN-γ) is an inflammatory cytokine that stimulates megakaryocyte development, and interferon regulatory factors (IRFs), IRF-1 and IRF-2 are typical transcription factors that are involved in the IFN-γ response. We investigate the role of IRFs in megakaryopoiesis. Mouse bone marrow hematopoietic stem cells (HSCs) were prepared and stimulated with IFN-γ. IFN-γ treatment induced IRF-2 expression as well as that of CD41 although induction levels of both were much lower than those of IRF-1. When IRF expression levels were studied in mouse bone marrow cell fractions, IRF-2 expression was relatively high in HSCs. An in vitro clonogenic assay showed that IRF-2 overexpressed cells increased the number of megakaryocytic colonies, but IRF-1 overexpressed cells did not, suggesting that IRF-2 is involved in megakaryopoiesis. Mechanistic analysis showed that IRF-2 transfection up-regulated CD41 promoter activity in hematopoietic cell lines through its binding to an ISRE-like site in the CD41 promoter. These findings suggest that IRF-2 plays an important role in megakaryocytic cell commitment or differentiation from HSCs by regulating CD41 expression under inflammation conditions.

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CXC chemokine ligand 14 (CXCL14) was first reported to be expressed in breast and kidney and thus called BRAK, but later found to be expressed various organs and tissues in vivo and cell cultures in vitro. For the first step to find tissue- and cell-type specific functions of CXCL14, we produced conditional knockout mice by Cre/lox P system and embryonic stem cells of the C57BL/6 mouse strain. By mating BMAC/cxcl14^+/flox with phosphoglycerokinase promoter-Cre mice followed by deletion of the Cre gene to avoid cleavage of putative cryptic/pseudo loxP site in the genome, we obtained systemic deletion of BMAC/cxcl14 gene. Intercrossing between male and female heterozygous mice (+/-) was performed; only 2.4% of the offspring were homozygous knockout mice, which was significantly lower than the expected Mendelian frequency, 25% (p<0.01). By inter-crossing cxcl14^+/flox mice with various tissue- or cell-type specific Cre mice, the cxcl14 loxP mouse will be useful for clarify tissue- or cell-type specific functions of cxcl14 in vivo.

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Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, is highly effective in experimental autoimmune encephalomyelitis (EAE) and decreases circulating mature lymphocytes by inhibiting S1P-dependent lymphocyte egress from secondary lymphoid organs. Infiltration of encephalitogenic CD4 T cells plays a critical role in the development and progression of EAE in mice. In this study, we investigated the effects of FTY720 on infiltration of interleukin 17 (IL-17)-expressing helper T cells (Th17 cells) and interferon-γ-expressing type 1 helper T cells (Th1 cells) into the spinal cords in EAE mice induced by immunization with myelin oligodendrocyte glycoprotein (MOG). Prophylactic treatment with FTY720 at an oral dose of 0.3 mg/kg significantly inhibited the development of EAE and markedly reduced the frequency of Th17 and Th1 cells in the spinal cords of EAE mice. On the contrary, the frequency of Th17 and Th1 cells in draining inguinal lymph nodes was increased to approximately 2-fold by FTY720, suggesting sequestration of myelin antigen-specific Th cells into draining lymph nodes. Moreover, we found that Th17 and Th1 cells could migrate toward 10 nM S1P and that the pretreatment with 1 nM FTY720-phosphate, an active metabolite of FTY720, almost completely inhibited S1P-induced migration of these Th cells. On the other hand, FTY720-phosphate up to 100 nM showed no clear effect on generation of these Th cells or cytokine production by them. From these results, the ameliorating effects of FTY720 on EAE are likely due to reduction of infiltration of encephalitogenic Th17 and Th1 cells into the central nervous system.

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