Common Features Of Am Expression And Secretion

The important features for AM expression and secretion are i) AM is expressed and secreted from the cells lacking secretory granules, and ii) pro-inflammatory cytokines, LPS, and growth factors regulate AM secretion. Another important point is that serious or lethal stress to the cells, such as hypoxia, augments AM expression and secretion. In the case of the endocrine type cells, AM stored in the granules are secreted immediately after stimulation. On the other hand, it usually takes 1-2 h after stimulation to observe a significant increase of AM expression and secretion in the non-endocrine type cells. These facts suggest that AM is mainly designed to elicit its effects as a local mediator.

Based on the regulation profiles of AM secretion, cultured cells can be classified into at least 3 classes. Class I consists of fibroblasts, VSMCs, ECs and oral KC. In this class, TNF, IL-1, LPS and glucocorticoid typically stimulate AM gene expression and secretion, while TGF-pj and IFN-y generally suppress them. Class II contains monocyte, macrophage and their related cells. The expression and secretion of AM from these cells are mainly regulated by the degree of differentiation into macrophage and by activation with LPS and inflammatory cytokines including IFN-y. Class III is tentatively separated from Classes I and II. AM secreted from the different classes is deduced to have distinct targets and effects. Oxygen and physical stresses are another important factors regulating AM gene expression and secretion. Among them, hypoxia is considered to be a strong and common stimulus. In the in vivo experiments, hypoxic, hemorrhagic and septic shock actually augmented gene expression of AM in many types of cells and tissues, and increased plasma AM concentration (Yoshibayashi, 1999; Ueda,

1999). Under the conditions that the cells are seriously damaged, such as inflammation and hypoxia, AM expression and secretion is confirmed to be dramatically enhanced both in vitro and in vivo systems.

AM is now known to elicit a wide range of biological activity including apoptosis-survival, angiogenic, anti-inflammatory and mitogenic/anti-mitogenic effects in addition to the vasodilatory effect (Kato 1997; Hague, 2000; Clementi 1999; Hinson, 2000). By the recent studies on AM-transgenic and knockout mice, mortality and tissue damage caused by endotoxin and oxidative stress are reported to be highly improved in the AM-overexpressing mice and to be exacerbated in the AM knockout mice (Shindo, 2000, Shimosawa, 2003; Niu, 2004). The regulation profile of AM expression and secretion as well as the ubiquitous expression of AM reveals that AM is not a classical peptide hormone but is a cytokine-like peptide regulating a wide range of cell function as a local mediator.

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