We examined the actions of sphingosine 1-phosphate (S1P) on signaling pathways in Chinese hamster ovary cells transfected with putative S1P receptor subtypes, i.e. Edg-1, AGR16/H218 (Edg-5), and Edg-3. Among these receptor-transfected cells, there was no significant difference in the expressing numbers of the S1P receptors and their affinities to S1P, which were estimated by [ 3 H]S1P binding to the cells. In vector-transfected cells, S1P slightly increased cytosolic Ca 2؉ concentration ([Ca 2؉ ] i ) in association with inositol phosphate production, reflecting phospholipase C activation; the S1P-induced actions were markedly enhanced in the Edg-3-transfected cells and moderately so in the AGR16-transfected cells. In comparison with vector-transfected cells, the S1P-induced [Ca 2؉ ] i increase was also slightly enhanced in the Edg-1-transfected cells. In all cases, the inositol phosphate and Ca 2؉ responses to S1P were partially inhibited by pertussis toxin (PTX). S1P also significantly increased cAMP content in a PTX-insensitive manner in all the transfected cells; the rank order of their intrinsic activity of S1P receptor subtypes was AGR16 > Edg-3 > Edg-1. In the presence of forskolin, however, S1P significantly inhibited cAMP accumulation at a lower concentration (1-100 nM) of S1P in a manner sensitive to PTX in the Edg-1-transfected cells but not in either the Edg-3 or AGR16-transfected cells. As for cell migration activity evaluated by cell number across the filter of blind Boyden chamber, Edg-1 and Edg-3 were equally potent, but AGR16 was ineffective. Thus, S1P receptors may couple to both PTX-sensitive and -insensitive G-proteins, resulting in the selective regulation of the phospholipase C-Ca 2؉ system, adenylyl cyclase-cAMP system, and cell migration activity, according to the receptor subtype.Sphingosine 1-phosphate (S1P), 1 one of the sphingolipid metabolites, has recently been suggested to affect a variety of cellular processes (1, 2). These cellular responses elicited by S1P have first been ascribed to the intracellular action of the lipid, because S1P accumulated in the cells in response to some kinds of cytokines, and moreover, S1P induced Ca 2ϩ mobilization in a cell-free system (3-5). On the other hand, these S1P-induced responses are also accompanied by the stimulation of several early signaling events that are usually regulated by cell-surface receptors. These signaling events include activation of PLC (6 -9), an increase in [Ca 2ϩ ] i (10 -12), regulation of adenylyl cyclase (6, 9, 10, 13), and Rho activation (14, 15). The presence of the latter mechanism has been supported by the recent identification of several cDNAs encoding G-protein-coupled receptors for S1P, i.e. Edg-1, AGR16/H218, and .The transfection experiments of these S1P receptor subtypes demonstrated that these putative S1P receptors can actually couple to multiple signaling pathways. Thus, the previous transfection experiments suggest the involvement of these putative S1P receptor subtypes in the regulation of multiple signal...

SUMMARYInflammatory cytokines are important for both cardiovascular scientists and practicing clinicians. Interleukin-6 (IL-6) has been emphasized by reports of elevated circulating as well as intracardiac IL-6 levels in patients with congestive heart failure (CHF). IL-6 may contribute to the progression of myocardial damage and dysfunction in chronic heart failure syndrome resulting from different causes. As the cause of CHF in cardiomyopathy, myocarditis, allograft rejection, and left ventricular assist device (LVADs) conditions, circulating IL-6 levels are associated with the severity of left ventricular dysfunction, and are also strong predictors of subsequent clinical outcomes. Continuous and excessive production of IL-6 promotes myocardial injury by breaking down both cytokine networks and viral clearance under viral myocarditis. Although IL-6 is likely important in the process of viral antigen presentation, early activation of immune responses and attenuation of viral replication also appear to be significant in an animal model of viral myocarditis. IL-6 can cause cardiac hypertrophy through the IL-6 signal transducing receptor component, glycoprotein 130. There are several interesting cases of cardiac myxoma complicated with mediastinal lymphadenopathy or left ventricular hypertrophy. Increased expression of IL-6 is observed in the myocardium of all donor hearts showing marked dysfunction. Myocardial IL-6 concentrations are also significantly higher in LVAD candidates compared with advanced heart failure patients. Although the IL-6 family plays a central role in the pathophysiology of cardiovascular diseases, it remains to be determined whether the IL-6 family is beneficial or detrimental. Future study will be needed to resolve this question. (Jpn Heart J 2004; 45: 183-193)

Traditional Chinese medicine (TCM) is a complete system of healing that developed in China about 3000 years ago, and includes herbal medicine, acupuncture, moxibustion and massage, etc. In recent decades the use of TCM has become more popular in China and throughout the world. Traditional Japanese medicine has been used for 1500 years and includes Kampo-yaku (herbal medicine), acupuncture and acupressure. Kampo is now widely practised in Japan and is fully integrated into the modern health-care system. Kampo is based on TCM but has been adapted to Japanese culture. In this paper we review the history and characteristics of TCM and traditional Japanese medicine, i.e. the selection of traditional Chinese herbal medicine treatments based on differential diagnosis, and treatment formulations specific for the 'Sho' (the patient's symptoms at a given moment) of Japanese Kampo--and look at the prospects for these forms of medicine.

No abstract

Tumor necrosis factor-alpha exacerbates myocardial I/R injury at an early stage of reperfusion by activating NF-kappaB, thereby inducing chemokines and adhesion molecules and facilitating leukocyte infiltration.