This review describes recent advances in studies of the inflammatory markers, high mobility group box 1 (HMGB1) and triggering receptor expressed on myeloid cells-1 (TREM-1). HMGB1 is a ubiquitous nuclear protein that is widely distributed among mammalian cells, passively released from necrotic cells and actively released from stimulated inflammatory cells. Released HMGB1 can bind to RAGE and/or TLRs and elicit inflammatory responses through the production of pro-inflammatory cytokines and chemokines. Extracellular levels of HMGB1 are increased in patients with various diseases including sepsis, cancer, ARDS, DIC, RA, acute coronary syndrome, heart failure and atherosclerosis. Thus, HMGB1 might function as an endogenous immune adjuvant and play a crucial role in the development of various inflammatory diseases. TREM-1 is a cell surface receptor expressed on phagocytes that can amplify inflammatory responses initiated by TLRs. Although a natural ligand for TREM-1 has not been identified, agonistic antibodies against TREM-1 can promote synergistic enhancement of TLR-medicated inflammatory responses. Furthermore, the expression of TREM-1 and soluble TREM-1 is increased in sepsis. These finding indicate that HMGB1 and TREM-1 might be useful inflammatory markers for the diagnosis and monitoring of various inflammatory diseases.

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Bone marrow stromal cells (MSCs) have great potential as therapeutic agents since they are easily isolated and can be expanded from patients without serious ethical or technical problems. Recently, new methods for the highly efficient and specific induction of functional neuronal cells and skeletal muscle cells have been found in MSCs. These induced cells were transplanted into animal models of spinal cord injury, stroke, Parkinson's disease and muscle degeneration, resulting in the successful integration of transplanted cells and improvement in the behavior of the transplanted animals. Here I describe the discovery of these induction systems and focus on the potential use of MSC-derived cells for neuro- and muscle-degenerative diseases.

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Multicellular processes of development and tissue regeneration are often sophisticatedly regulated by the spatial arrangement of extracellular matrix and signaling molecules in a time- and concentration-dependent manner. Concentration gradients of biomolecules such as growth factors and transcriptional factors play a pivotal role in the in vivo induction and formation of tissues and organs with complex structural architecture. It is therefore conceivable that a three-dimensional bioengineered scaffold with a spatial gradient of biomolecules could allow cells to induce regeneration of tissue with the natural morphological structure. This mini review article overviews fabrication techniques for functional gradient materials, and several concrete examples are introduced to emphasize importance of gradient materials in tissue engineering.

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Periodontitis is a chronic inflammatory disease associated with degradation of periodontal tissues and is highly prevalent in late middle age.
Statins, such as simvastatin, are pharmacologic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that inhibit cholesterol synthesis, which is important in development of arteriosclerosis. Many cardiovascular studies have suggested that statins also have anti-inflammatory effects which are independent of cholesterol lowering. As a chronic inflammatory disease, periodontitis shares some mechanisms with atherosclerosis. Since oral epithelial cells are implicated in periodontal inflammation, we measured simvastatin effects on cytokine [interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor α (TNFα)] production by cultured human epithelioid cell line KB cells in response to IL-1α. Simvastatin decreased production, an effect reversed by adding mevalonate or geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP). Simvastatin was found to reduce NF-κB and AP-1 promoter activity in KB cells. Our results support an anti-inflammatory effect of simvastatin on human oral epithelial cells.

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The endothelial cell-specific granule Weibel-Palade body releases vasoactive substances capable of modulating vascular inflammation, thrombosis and atherogenesis. Pathogen recognition by endothelial Toll-like receptors (TLRs) is thought to play a crucial role in promotion of vascular inflammatory responses. However, the molecular basis for the early-phase responses of endothelial cells to pathogens has not been fully elucidated. We found that human aortic endothelial cells respond to several TLR ligands, including bacterial lipoteichoic acids and lipopeptides, but not lipopolysaccharides, to induce Weibel-Palade body exocytosis, accompanied by release of the storage component von Willebrand factor. In this mini-review, we briefly describe a novel function of endothelial TLRs and discuss its implications in aortic inflammation or atherogenesis.

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The quiescent state in the cell cycle is thought to be indispensable for the maintenance of hematopoietic stem cells (HSCs). The interaction between HSCs and their niche is critical for maintaining the stem cell properties of HSCs, including self-renewal capacity and the ability of differentiation into single or multiple lineages. The niche cells produce signaling molecules, extracellular matrix, and cell adhesion molecules, and regulate stem cell fates. HSCs balance quiescence and cell division in the stem cell niche for long-term sustaining of hematopoiesis in the niche. Recently, long-term repopulating (LT)-HSCs exist frequently in endosteal surface of trabecular bone area in bone marrow (BM), and it was clarified that an osteoblastic cells function as a niche cells for HSCs. The specific properties of HSC are dynamically controlled by the signalings of receptor/ligand and cell adhesion molecules produced by osteoblastic cells.
We have recently reported that side-population (SP) cells in HSCs are in the quiescent state of cell cycle. Cell adhesion of HSCs to the osteoblastic niche enhanced the ability of HSCs to become quiescent, resulting in protection of the HSC compartment from stresses suppressing hematopoiesis.

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Ischemia-reperfusion injury occurred in the kidneys in the cases of renal transplantation and hypovolemic shock causes severe inflammation and tissue damage of the kidneys, resulting in the acute rejection and renal failure. Recently, apoptosis following the inflammation has been reported to play a key role in the tissue damage. Inhibition of Fas/FasL-mediated signal which plays a central role in the apoptosis effectively protected the tissue from ischemia-reperfusion injury. Fas-Fc, ZVAD-fmk, Fas siRNA, and anti-FasL antibody significantly decreased the number of apoptotic cells, attenuated the tissue injury and reduced mortality. Because some of these agents were effective even they were given after ischemia-reperfusion, they may be potent agents to ameliorate the apoptosis-induced renal tissue injury.

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