Branched chain amino acids enhance the maturation and function of myeloid dendritic cells ex vivo in patients with advanced cirrhosis.
An imbalance of plasma amino acids is observed in patients with advanced cirrhosis. The aim of this study was to investigate the influence of the extracellular amino acid imbalance on the function of myeloid dendritic cells (DCs) in patients with advanced cirrhosis. We made a serum-free culture medium consistent with the average concentration of plasma amino acids from healthy controls (HC, n = 25) or patients with advanced cirrhosis (LC, n = 43) to reflect more closely the actual environment of the living body. We compared the phenotypical and biological functions of blood dendritic cells antigen-positive dendritic cells (BDCA+ DCs) and monocyte-derived dendritic cells (MoDCs) from LC and HC with these media. After adding stimulants, the CD83 and CD86 expressions of DCs from LC were lower than those from HC. In both HC and LC, both CD83 and CD86 expressions of DCs stimulated under the cirrhotic medium were lower than under the control medium. This phenomenon was accompanied by a suppression of the mammalian target of rapamycin (mTOR)/S6K-signaling pathways. The interleukin 12 (IL-12) production in the cirrhotic medium was significantly lower than in the control medium and increased when valine or leucine was added to the medium. In patients with advanced cirrhosis, peripheral blood mononuclear cells stimulated in the autologous plasma after oral administration of branched-chain amino acid (BCAA) granules had significantly increased interferon gamma production.


CONCLUSIONS
In advanced cirrhosis, there is impairment of the function and maturation of DCs, which has been shown to be related to an imbalance in the extracellular amino acid profile. Elevating the extracellular concentration of BCAAs ex vivo in patients with advanced cirrhosis improved the function of DCs.
Kakazu
Eiji
E
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ueno
Yoshiyuki
Y
Kondo
Yasuteru
Y
Fukushima
Koji
K
Shiina
Masaaki
M
Inoue
Jun
J
Tamai
Keiichi
K
Ninomiya
Masashi
M
Shimosegawa
Tooru
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000597:Amino Acids, Branched-Chain / Q000097:blood / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008103:Liver Cirrhosis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D000597:Amino Acids, Branched-Chain; D018664:Interleukin-12; D007371:Interferon-gamma; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases