Abstract-To clarify the role of histamine-producing cells and its origin in atherosclerosis, we investigated histidine decarboxylase (HDC; histamine-producing enzyme) expression in murine arteries with vascular injuries after the animal had received transplanted bone marrow (BM) from green fluorescent protein (GFP)-transgenic mice. The neointima in the ligated carotid arteries contained BM-derived HDC ϩ cells that expressed macrophage (Mac-3) or smooth muscle cell antigen (␣-SMA). In contrast, the HDC ϩ BM-derived cells, which were positive for Mac-3, were mainly located in the adventitia in the cuff replacement model. In apolipoprotein E-knockout mice on a high cholesterol diet, BM-derived cells expressing Mac-3 in the atheromatous plaques were also positive for HDC. In comparison with wild-type mice, HDC Ϫ/Ϫ mice showed reduced neointimal thickening and a decreased intima-to-media ratio after ligation and cuff replacement. These results indicate that histamine produced from BM-derived progenitor cells, which could transdifferentiate into SMC-or macrophage-like cells, are important for the formation of neointima and atheromatous plaques. Key Words: histamine Ⅲ histidine decarboxylase Ⅲ progenitor cells Ⅲ bone marrow Ⅲ vascular injury H istidine decarboxylase (HDC) is a rate-limiting enzyme for the production of histamine from L-histidine. Histamine plays an important role in allergy, inflammation, neurotransmission, and gastrointestinal functions by acting via specific histamine receptors. 1,2 With regards to the atherosclerotic coronary artery, histamine is a vasoconstrictor, and the accumulation of activated mast cells in the adventitia and ruptured plaques in acute coronary syndrome has been reported. [3][4][5] Another histamine-producing cell in the atherosclerotic lesion is the macrophage, 6 which is present in all stages of atherosclerosis and is a major cellular constituent of atheromatous plaques. Previously, we demonstrated that HDC is expressed in CD68 ϩ foam cells (macrophages) of human atherosclerotic lesions. 6 In monocytic human U937 cells, the expression of HDC and histamine H1 receptor (HH1R) is induced during macrophage differentiation, 6,7 and granulocyte macrophage-colony stimulating factor, one of the proinflammatory and macrophage-differentiation factors produced in the atherosclerotic lesions, 8 is also able to induce HDC and HH1R. 9 As a longer-term effect, histamine stimulates cultured human intimal smooth muscle cells (SMCs) to proliferate and to express matrix metalloproteinase-1 (MMP-1). 10 Histamine also upregulates the gene expression of endothelial nitric oxide synthase (eNOS) in vascular endothelial cells (ECs). 11 These histamine effects are all mediated via HH1R, which is expressed in the ECs, foam cells, and SMCs of human atherosclerotic lesions. 12 In the case of monocytes, we have reported that histamine upregulates lipopolysaccharideinduced expression of tumor necrosis factor-␣ (TNF-␣) during macrophage differentiation and switching of the histamine receptor from histamine H...

Monocyte migration is one of the key events occurring in the early stage of atherosclerosis. This process includes monocytic adhesion to and penetration through the arterial intima. In such an environment, many factors stimulate the monocytes to enhance integrin activation and extracellular matrix degradation. To investigate the coordinative operation of these two events in relation to monocyte migration, we paid particular attention to the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on monocytes in terms of RhoA activation and matrix metalloproteinase (MMP) expression. RhoA and integrin clustering were activated by GM-CSF, monocyte chemoattractant protein-1 (MCP-1) and platelet-derived growth factor-BB (PDGF-BB) in human monocytic cell lines. Furthermore, enhancement of migration was observed with stimulation by MCP-1 and PDGF-BB. Granulocyte-macrophage colony-stimulating factor did not enhance the migration, even though it activated RhoA and integrin. However, GM-CSF is known to stimulate monocytes to express MCP-1, suggesting the presence of an indirect mechanism for GM-CSF-mediated migratory activity. In contrast, only GM-CSF enhanced the expression of MMP-1 and MMP-9. These results provide evidence that GM-CSF has multiple functions enhancing monocytic migration via RhoA and integrin activation, and via MMP expression.

A case of primary leiomyosarcoma of a thoracic vertebra associated with a compression fracture in a 75-year-old woman was preoperatively thought to be granulation tissue. Surgical decompression was performed and the histological and immunohistochemical studies established the diagnosis of leiomyosarcoma. Based on the clinical and radiological examinations, metastases were ruled out. Primary leiomyosarcoma of the vertebra is extremely rare and in that site it is considered to have a relatively poor prognosis.

Y-box-binding proteins are members of the human cold-shock domain protein superfamily, which includes dbpA, dbpB/YB-1, and dbpC/contrin. dbpC/contrin is a germ cell-specific Y-box-binding protein and is suggested to function as a nuclear transcription factor and RNA-binding protein in the cytoplasm. Whereas ubiquitous dbpB/YB-1 expression has been well studied in various types of human carcinomas as a prognostic or predictive marker, the dbpC/contrin expression in human tumour cells has not been reported. In this report, we provide the first evidence showing that dbpC was highly expressed in human testicular seminoma and ovarian dysgerminomas, and in carcinomas in other tissues and that its expression in normal tissues is nearly restricted to germ cells and placental trophoblasts. These results indicate that dbpC/contrin would be a potentially novel cancer/testis antigen.