〈Review〉Target validation and drug discovery for in flammatory diseases

[Abstract] We have examined to find new factors, which are involved in inflammatory diseases including ischemic diseases. To investigate the mechanism of inflammation, we have proved that monocyte/macropharge plays roles in the up-stream of immune responses. Binding adhesion molecules on monocyte/macropharge and T-cell induces the activation of these cells. It is reported that monocyte/macropharge releases histamine, prostaglandin (PG)E2, interleukin (IL)-18 and high mobility group box-1 (HMGB1). We have found that these mediators regulate immune responses. Therefore, we suggested that histamine, IL-18 and HMGB1 are target for new treatment of inflammatory diseases. In the present review, I explain my findings as the followings

Histamine Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-␣ Production in an Intercellular Adhesion Molecule-1- and B7.1-Dependent Manner

ABSTRACT Lipopolysaccharide (LPS) is recognized as a key molecule in the pathogenesis of Gram negative sepsis and septic shock. In the present study, we demonstrate that LPS (1-1000 pg/ml) concentration dependently up-regulated the expression of intercellular adhesion molecule (ICAM)-1, B7.1, and B7.2 on human monocytes using fluorescence-activated cell sorting analysis, and that tumor necrosis factor (TNF)-␣ production induced by LPS in peripheral blood mononuclear cells (PBMCs) was inhibited by the addition of antibodies against these adhesion molecules, suggesting the dependence of TNF-␣ production on cell-cell interaction through these adhesion molecules. Moreover, we found that histamine (10 Ϫ7 -10 Ϫ4 M) concentration dependently inhibited the expression of ICAM-1 and B7.1, but not B7.2 on monocytes induced by LPS. Histamine also inhibited the responses of TNF-␣ production induced by LPS. The modulatory effects of histamine on ICAM-1 and B7.1 expression and TNF-␣ production were all concentration dependently antagonized by famotidine but not by d-chlorpheniramine and thioperamide, and were mimicked by selective H2-receptor agonists but not by H1-, H3-, and H4-receptor agonists, indicating the involvement of H2-receptors in the histamine action. Dibutyryl cAMP down-regulated ICAM-1 and B7.1 expression on monocytes stimulated by LPS, suggesting the mediation by the cyclic adenosine monophosphate-protein kinase A pathway of H2-receptor activation. These results as a whole indicated that histamine via H2-receptor inhibited the LPS-induced TNF-␣ production through the regulation of ICAM-1 and B7.1 expression, leading to the reduction of innate immune response stimulated by LPS

Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production and lymphocyte proliferation during human mixed lymphocyte reaction

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The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets

Advanced glycation end-products (AGEs) are produced by non-enzymatic glycation between protein and reducing sugar such as glucose. Although glyceraldehyde-derived AGEs (Glycer-AGEs), one of the AGEs subspecies, have been reported to be involved in the pathogenesis of various age-relating diseases such as diabetes mellitus or arteriosclerosis, little is known about the pathological and physiological mechanism of AGEs in vivo. In present study, we produced 4 kinds of polyclonal antibodies against AGEs subspecies and investigated the localization of AGEs-modified proteins in rat peripheral tissues, making use of these antibodies. We found that Glycer-AGEs and methylglyoxal-derived AGEs (MGO-AGEs) were present in pancreatic islets of healthy rats, distinguished clearly into the pancreatic α and β cells, respectively. Although streptozotocin-induced diabetic rats suffered from remarkable impairment of pancreatic islets, the localization and deposit levels of the Glycer- and MGO-AGEs were not altered in the remaining α and β cells. Remarkably, the MGO-AGEs in pancreatic β cells were localized into the insulin-secretory granules. These results suggest that the cell-specific localization of AGEs-modified proteins are presence generally in healthy peripheral tissues, involved in physiological intracellular roles, such as a post-translational modulator contributing to the secretory and/or maturational functions of insulin