Macrophages or mononuclear phagocytes are heterogeneous populations present throughout the body which can adapt quite dramatically to the surrounding milieu, both in the steady state and during immune/inflammatory responses. To assist in our understanding of this diversity, they have been classified into polarization or “activation” states, termed M1 and M2, respectively. This in vitro classification commonly incorporates interferon γ (± lipopolysaccharide) as the stimulus for M1 macrophages and IL-4 or IL-13 for M2 macrophages. Attempts are underway to place tissue macrophages, isolated from ongoing immune/inflammatory reactions, into these categories. However, more flexible classifications are needed to take into account the diversity of macrophage functions. We have compared the in vitro properties of monocytes/macrophages treated with macrophage-colony stimulating factor (M-CSF or CSF-1) and granulocyte macrophage-CSF (GM-CSF), the former because of its role in macrophage lineage development in the steady state and the latter because of its proinflammatory and immune-potentiating properties. Data will be presented on “M2-like” properties of CSF-1-treated populations and “M1-like” features of the GM-CSF-treated counterparts with links to IL-12 family biology. It is proposed that such CSF-dependent changes should be considered in discussions of macrophage polarization. The concept of “CSF-1 resistance” in macrophages, whereby steady state CSF-1-dependent signaling has to be overcome by pro-inflammatory stimuli, such as GM-CSF, interferon γ etc, will be discussed.

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The multiple soluble ligands such as cytokines play a pivotal role in the pathogenesis of inflammatory diseases. The appropriate intracellular signaling pathways must be activated via cytokine receptors on the cell surface and the tyrosine kinase transduce the first “outside to in” signals to be phosphorylated following receptor binding to its ligand. Among them, members of Janus kinase (Jak) family and Spleen tyrosine kinase (Syk) family are essential for the signaling pathways of various cytokines and are implicated in the pathogenesis of rheumatoid arthritis (RA), a representative autoimmune inflammatory disease. Selective inhibition of Jak3 was considered as a potential target in the treatment of RA and an orally available Jak3 inhibitor CP-690,550 (tofacitinib), is currently in clinical trials for RA with satisfactory effects and acceptable safety. Our in vitro experiments have indicated that the inhibition could be mediated through the suppression of IL-17 and IFN-γ production and proliferation of CD4⁺ T cells without directly affecting synovial fibroblasts and monocytes. Multiple global clinical examinations indicate that JAK inhibition with CP-690,550 in patients with RA results in rapid and remarkable clinical effects without severe adverse events. A selective Syk inhibitor R788 (fostamatinib) has been shown to be effective for the treatment of not only RA but also bronchial asthma, B-cell lymphoma and idiopathic thrombocytopenic purpura. We have found that Syk-mediated B cell receptor (BCR)-signaling is prerequisite for optimal induction of toll-like receptor (TLR)-9, thereby allowing efficient propagation of CD40 and TLR9-signaling in human B cells. These results indicate that inhibition of Syk have a potential to regulate B-cell mediated inflammatory diseases such as systemic lupus etythematosus (SLE). We here document the in vitro and in vivo effects of a Jak inhibitor and a Syk inhibitor for the treatment of autoimmune inflammatory diseases, mainly RA and SLE.

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It is generally believed that atherosclerosis is a chronic inflammatory disease that is promoted by lifestyle-related diseases, such as hypertension, dyslipidemia, and diabetes. The renin-angiotensin system (RAS) has been demonstrated to play a critical role in the initiation and progression of atherosclerosis, thereby contributing to development of cardiovascular diseases. Angiotensin II (Ang II), a major substrate in RAS, stimulates atherosclerosis through various deleterious effects such as endothelial dysfunction, cellular proliferation and inflammation. Reactive oxygen species (ROS) play a major role in the athero-promoting actions of Ang II. In fact, recent basic and clinical studies demonstrated that pharmacological inhibition of renin-angiotensin system is effective in prevention of atherosclerotic diseases. Elucidation of molecular mechanism of chronic inflammation should lead to development of effective strategies against lifestyle-related diseases.

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Epithelial cells constitute the tissue structure and also play indispensable roles in various organs, including skin, lung, and the digestive tract. Besides acquiring tissue-specific functions, their common and most important role is to serve as a physical barrier between inner- and outer- environment. Upon inflammation of its resident tissue, the continuous structure of the epithelial layer is often disrupted, which results in loss of static environment in inner side of the tissue. Such a change in the inner environment may act as a key event to drive further exacerbation and persistence of the local inflammation. Thus, proper regeneration to restore the continuity of the epithelial layer is a prerequisite to give an end to the initiated inflammation. In this special issue, we would like to overview what we now know about how tissue regeneration is executed in various tissues, under inflammatory environment. Further studies may reveal how the inflammatory environment, both at cellular and molecular level, modulates tissue regeneration and give the basis for the establishment of therapeutic approach directed to tissue regeneration in various inflammatory diseases.

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Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, are characterized not only by the sub-mucosal accumulation of inflammatory cells, but also by the severe damage of the epithelial layer. Recent clinical studies have featured “mucosal healing” as the most significant prognostic factor for long-term remission in IBD patients, suggesting that accomplishment of epithelial regeneration is critically required to improve the treatment for IBD. From series of recent studies, we now know that several key molecular pathways dominantly regulate not only the homeostasis, but also the repair process of the intestinal epithelium. Future studies may allow us to facilitate regeneration of the damaged intestinal epithelia, either by molecular-based manipulation of endogenous regenerative signals, or by a tissue-engineering based strategy utilizing ex-vivo expansion of primary intestinal epithelial cells.

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Some congenital skin disorders lacking structure proteins in the basement membrane zone carry severe prognosis because of severe erosion and skin dysfunction on the whole body. So far, several therapeutic strategies have been emerging for such disorders: 1. gene therapies, 2. protein therapies and 3. cell therapies. Cell therapies have a potential to affect skin systemically, and stem cell transplantation is one of the most hopeful candidates for treating severe congenital skin disorders such as epidermolysis bullosa, from a perspective of transdifferentiation and re-programming of stem cells. We review here the recent strategies and progress of stem cell transplantation for epidermolysis bullosa.

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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an acute-onset neutrophil-dominant inflammatory lung disease caused by or associated with various illness and injuries. The mortality rate related to this disorder can be as high as 40%. In contrast, idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) is a chronic progressive inflammatory lung disease of unknown etiology, with a mean survival of five years. There are no established treatments for either disease and novel therapies are eagerly desired. Lung epithelial cells were initially discovered to be derived from bone marrow stem cells and progenitor cells. As a result of progress made in regenerative medicine, several types of tissue stem cells and progenitor cells have been identified in the lungs, each of which is involved in tissue repair and regeneration at different levels of the bronchial tree. In terminal bronchioles and alveoli, where lung cells are specifically vulnerable to injuries caused by inflammatory cells, Clara cell-specific protein-positive epithelial cells, including bronchioalveolar stem cells, and a subgroup of alveolar epithelial type II cells, have been identified as lung tissue stem cell and progenitor cell candidates. Intratracheal administration of alveolar epithelial type II cells or epithelial progenitor cells has been shown to be effective in animal models of ALI/ARDS and IPF/UIP. As a novel strategy based on regenerative medicine, this could be a promising approach to treat inflammatory lung diseases.

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Behcet's disease (BD) is a multisystem inflammatory disease that is characterized by recurrent attacks of uveitis, oral apthous ulcers, genital ulcers, and erythema nodosum. The etiology and pathogenesis of BD are largely unknown. We have presented evidence that supports a role of excessive Th1 cell activity in BD. Recently, it has been suggested that Th17 cells are associated with several autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, all of which are considered to be Th1 diseases. Therefore, it is interesting to study the role of Th17-related cytokines and Th17-associated signaling molecules in BD. Major Th17-related cytokines were not detected in peripheral blood mononuclear cells (PBMCs) and in skin lesions of BD patients. Expression of TGF-beta receptor and Smad2 mRNA was significantly higher in BD patients compared with the levels in normal controls. Interleukin (IL)-23 receptor, ROR-C, and Foxp3 are key transcription factors expressed by Th17 cells and regulatory T cells, respectively, and their expression was decreased in BD. These findings suggest that T cell function may be unbalanced in BD.

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Biodevices are implanted for long periods of time, so the release of metal ions from alloys should be tested in tissues to assess the risk of inducing metal allergies. However there is little evidence that the release of metal ions from alloys in vivo is similar to that in vitro. We implanted metal wires in mice and determined the concentration of metal ions in tissue to analyze the mechanisms responsible for metal allergies. The release of ions from the Ni wire was detected within 8 h and attained a plateau 72 h after the implantation. Furthermore, it was significantly increased by an injection of LPS. The results indicated that the release of Ni was apparently enhanced by inflammatory responses. We also established an in vitro assay system using the murine macrophage cell line RAW 264. The addition of LPS apparently increased the amount of Ni released into the medium, indicating the activation of the cells to have enhanced the elution of ions from the Ni plate. Our in vitro model using LPS-stimulated RAW264 cells might reflect the elution of Ni in inflamed tissue.

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FTY720 (FTY) is a new immunosuppressant which modulates sphingosine 1-phospate receptors. FTY has been shown to be highly effective to multiple sclerosis in clinical studies. Recently, we reported the effects and the mechanisms by which FTY inhibited arthritis in rheumatoid arthritis model of SKG mice. Here, we briefly review up to date reports of FTY including our experimental results.

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Recently, it has been shown that bone marrow (BM)-derived hematopoietic cells have critical roles in the tumor microenvironment as a major components of tumor stroma and regulate tumor progression. In addition, hematopoietic cells need chemokine signaling for their recruitment. On the other hand, COX-2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis. However, their precise mechanisms in stromal formation and angiogenesis remain elusive. Our recent data suggest that COX-2 inhibition reduced CXCL12/CXCR4 expression as well as tumor stromal formation, tumor-associated angiogenesis and tumor growth. Consistently, PGE₂ enhanced stromal formation, angiogenesis and CXCL12/CXCR4 expression. Moreover, a COX-2 inhibitor suppressed expression of a fibroblast marker (S100A4) in tumor stroma. These suppressive activities were found by either EP3 or EP4 knockout among 4 PGE2 receptors. Experiments using GFP-bone marrow chimeric mice revealed that CXCL12⁺CXCR4⁺S100A4⁺ fibroblasts dominantly composed stromal cells and most of which were recruited from BM. Additionally, fibroblasts were stimulated to produce CXCL12 by either EP3 or EP4 specific agonist in vitro. Therefore, COX-2/PGE₂-EP3/EP4 signaling may play a crucial role in tumor stromal formation and angiogenesis via CXCL12/CXCR4 chemokine system. These results may lead to new approaches in further studies and cancer treatment.

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Interleukin-6 (IL-6) plays essential roles not only in the immune response, but also in hematopoiesis, and in the central nervous system. Dysregulated production of IL-6 has been found in chronic inflammatory autoimmune diseases such as rheumatoid arthritis (RA). Many reports have indicated that lipid levels, such as total cholesterol and triglyceride levels, are changed under inflammatory conditions; this is also observed in RA patients. It is well-established that IL-6 affects lipid metabolism in animals and humans, and it has been reported that blockade of IL-6 decreases lipid levels in RA patients. Based on the above findings, we investigated how IL-6 may change lipid metabolism. We conclude that it is likely that these IL-6-mediated changes in lipid metabolism are at least partly responsible for the lipid profile changes following IL-6 blockade in RA patients.

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