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Extracellular Branched-Chain Amino Acids, Especially Valine, Regulate Maturation and Function of Monocyte-Derived Dendritic Cells¹

Eiji Kakazu^*, Noriatsu Kanno, Yoshiyuki Ueno^2,* and Tooru Shimosegawa^*

^* Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan; and Division of Gastroenterology, Iwai General Hospital, Iwate, Japan

The functions of dendritic cells (DCs) are impaired in patients with liver cirrhosis. It is well-known that cirrhotic patients show decreased levels of plasma branched-chain amino acids (BCAA). Although amino acids are associated with maintaining the cell structure and function in many organs, limited data are available regarding the role of amino acids including BCAA in the immune system. We aimed to investigate the roles of BCAA in the function of human monocyte-derived DCs (MoDC). CD14-positive monocytes (CD14 ⁺) were isolated from PBMC from healthy volunteers and hepatitis C virus (HCV) cirrhotic patients. In medium deprived of BCAA or valine, monocytes were able to differentiate into immature, but not into mature, DCs and showed weak expression of CD83. The deprivation of leucine or isoleucine did not affect this process. The MoDC allostimulatory capacity was significantly decreased in medium deprived of BCAA or valine (p = 0.017, p = 0.012, Bonferroni’s analysis, respectively). Annexin V^FITC/propidium iodide staining showed that the DC yield and viability were not significantly different under any medium. Immunoblotting demonstrated that depletion of valine or leucine decreased phospho-S6 kinase expression. Valine increased dose-dependently the allostimulatory capacity and IL-12 production of MoDC from both healthy volunteers and HCV cirrhotic patients. An elevated extracellular concentration of valine could improve the DC function in cirrhotic patients. These data provide a rationale for nutrition therapy that could be beneficial to patients with cirrhosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Health and Labour Sciences Research Grants (from the Ministry of Health, Labour, and Welfare of Japan) for the Research on Measures for Intractable Diseases and Grant-in-Aid for Scientific Research C (17590609) from the Japan Society for the Promotion of Science (to Y.U.).

² Address correspondence and reprint requests to Dr. Yoshiyuki Ueno, Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai, 980-8574 Japan. E-mail address: yueno{at}mail.tains.tohoku.ac.jp

³ Abbreviations used in this paper: HCV, hepatitis C virus; BCAA, branched-chain amino acid; mTOR, mammalian target of rapamycin; DC, dendritic cell; MoDC, monocyte-derived DC; CCM, complete culture medium; FSC, forward light scatter; SSC, side light scatter; PI, propidium iodide; MFI, mean fluorescence intensity.