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★ Glutamine showed an inhibitory effects on TNF-α and IL-6 in LPS-stimulated human monocytes. ★ Alanine had contrary effects on IL-6 and comparable impact on TNF-α in septic monocytes. ★ Using flow cytometry neither amino acid affected IL-8 production in septic human monocytes. ★ By combining glutamine and alanine, the inhibitory effect on TNF-α was enhanced. ★ The suppressing impact of glutamine on IL-6 by additionally disposed alanine was attenuated.To investigate the effects of the commonly-used immunomodulators L-glutamine, L-alanine, and the combination of both L-alanyl-L-glutamine (Dipeptamin®) on intracellular expression of IL-6, IL-8, and TNF-α during endotoxemia, lipopolysaccharide (LPS)-stimulated human monocytes in a whole blood system were investigated by flow cytometry.Whole blood of twenty-seven healthy volunteers was stimulated with LPS and incubated with three different amino acid solutions (1. L-glutamine, 2. L-alanine, 3. L-alanyl-L-glutamine, each concentration 2 mM, 5 mM, incubation time 3 h). CD14+ monocytes were phenotyped in whole-blood and intracellular expression of cytokines was assessed by flow cytometry.Our investigations showed for the first time in whole blood probes, imitating best physiologically present cellular interactions, that L-glutamine caused a dose-independent inhibitory effect on IL-6 and TNF-α production in human monocytes stimulated with LPS. However, L-alanine had contrary effects on IL-6 expression, significantly upregulating expression of IL-6 in LPS-treated monocytes. The impact of L-alanine on the expression of TNF-α was comparable with glutamine. Neither amino acid was able to affect IL-8 production in LPS-stimulated monocytes. The combination of both did not influence significantly IL-6 and IL-8 expression in monocytes during endotoxemia, however strongly reduced TNF-α production.For the regulation of TNF-α, L-glutamine, L-alanine and the combination of both show a congruent and exponentiated downregulating effect during endotoxemia, for the modulation of IL-6, L-glutamine and L-alanine featured opposite regulation leading to a canceling impact of each other when recombining both amino acids.