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

Abstract

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 VFITC/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.

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

“…Precedence for a clinically relevant role for amino acids in the modulation of immune responses exists (46,47). For DC, it has been shown that branched-chain amino acids affect maturation, and it has been proposed that this modulation is a consequence of inhibition of the mTOR pathway (30). Our results are consistent with this hypothesis but extend the concept to arginine.…”

“…These data suggest that arginine levels, similar to what has been shown for branched-chained amino acids (30), affect mTOR activity in moDC but also indicate a difference between amino acids.…”

“…Previous studies suggested an inhibitory effect of branched-chain amino acids on the mTOR/S6K signaling pathway, resulting in impaired maturation of moDC and particularly affecting CD83 expression (30). mTOR is a serine/threonine kinase that is present in two distinct protein complexes, mTORC1 and mTORC2.…”

Changes in barrier health status of the gill for grass carp (Ctenopharyngodon idella) during valine deficiency: Regulation of tight junction protein transcript, antioxidant status and apoptosis-related gene expression

“…However, there is no information regarding the effects of valine on pro-cytokine in the fish gill. In human, valine deficiency could inhibit the maturation of dendritic cells (DCs) [17]. In mouse, immature DCs exhibited higher amounts of interleukin-1a (IL-1a), IL-1b and TNF-a mRNA [18].…”

Nutritional value of the protein of consumer carp Cyprinus carpio L.

“…This indicated that the amino acid limiting the nutritional value of the protein of the studied carps was valine, yet it must be stressed that the obtained CS values for this exogenous amino acid must be considered very high. This is important because deficiencies of valine can cause disorders in the coordination of movements, body mass decrease, lack of appetite (Gertig & Przysławski 2006) and its appropriate amount has a positive effect on the (Kakazu et al 2007). The calculated values of the CS index also indicate that almost 100% of the exogenous amino acids from carp protein can be used for synthesis of systemic proteins.…”