Ethyl pyruvate and ethyl lactate down-regulate the production of pro-inflammatory cytokines and modulate expression of immune receptors.
Esters of alpha-oxo-carbonic acids such as ethyl pyruvate (EP) have been demonstrated to exert inhibitory effects on the production of anti-inflammatory cytokines. So far, there is no information about effects, if any, of ethyl lactate (EL), an obviously inactive analogue of EP, on inflammatory immune responses. In the present study, we provide evidence that the anti-inflammatory action of alpha-oxo-carbonic acid esters is mediated by inhibition of glyoxalases (Glo), cytosolic enzymes that catalyse the conversion of alpha-oxo-aldehydes such as methylglyoxal (MGO) into the corresponding alpha-hydroxy acids using glutathione as a cofactor. In vitro enzyme activity measurements revealed the inhibition of human Glo1 by alpha-oxo-carbonic acid esters, whilst alpha-hydroxy-carbonic acid esters such as EL were not inhibitory. In contrast, both EP and EL were shown to suppress the Lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and IL-8 from human immunocompetent cells, and modulated the expression of the immune receptors HLA-DR, CD14 and CD91 on human monocytes. Here, we show a crossing link between glyoxalases and the immune system. The results described herein introduce glyoxalases as a possible target for therapeutic approaches of immune suppression.
Hollenbach
Marcus
M
University of Leipzig, Institute of Biochemistry, Johannisallee 30, 04103 Leipzig, Germany.
Hintersdorf
Anja
A
Huse
Klaus
K
Sack
Ulrich
U
Bigl
Marina
M
Groth
Marco
M
Santel
Thore
T
Buchold
Martin
M
Lindner
Inge
I
Otto
Andreas
A
Sicker
Dieter
D
Schellenberger
Wolfgang
W
Almendinger
Johannes
J
Pustowoit
Barbara
B
Birkemeyer
Claudia
C
Platzer
Mathias
M
Oerlecke
Ilka
I
Hemdan
Nasr
N
Birkenmeier
Gerd
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007773:Lactates / Q000494:pharmacology*; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D011765:Pyruvaldehyde / Q000494:pharmacology; D011773:Pyruvates / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007773:Lactates; D011773:Pyruvates; D011971:Receptors, Immunologic; C046522:ethyl pyruvate; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase; C015866:ethyl lactate