Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-α (TNF-α) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils.

Abstract

Kynurenic acid (KynA), a broad spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The potential anti-inflammatory effect of KynA in human leukocytes has not been characterized. The aim of this study was to compare the effects of KynA with those of a new analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride on tumour necrosis factor-α (TNF-α) production and high mobility group box protein 1 (HMGB1) secretion. The effects of KynA on granulocyte activation were investigated via the secretion of human neutrophil peptide 1-3 (HNP1-3). Peripheral blood mononuclear cells and granulocytes or CD14 positive monocytes were applied as effector cells, or whole blood cultures were used. TNF-α, HMGB1 and HNP1-3 concentrations were determined by ELISA, TNF-α and HNP1-3 mRNA expressions were quantified by reverse transcription PCR. KynA attenuated the TNF-α production of human mononuclear cells activated by heat-inactivated Staphylococcus aureus, inhibiting TNF-α production at the transcription level. Furthermore, KynA diminished HMGB1 secretion by U 937 monocytic cells and by peripheral blood monocytes. KynA inhibited the HNP1-3 secretion in whole blood and in granulocyte cultures. The suppressive effect of the KynA analogue was more potent than that of an equimolar concentration KynA in TNF-α, HMGB1 and HNP1-3 inhibition. These results suggest that the new KynA analogue has a more potent immunoregulatory effect than KynA on human mononuclear cells, monocytes and granulocytes and indicate the potential benefits of further exploration of its uses in human inflammatory disease.

• Authors: Zoltán Tiszlavicz, Balázs Németh, Ferenc Fülöp, László Vécsei, Katalin Tápai, Imre Ocsovszky, Yvette Mándi
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 383 Issue 5 Pg. 447-55 (May 2011) ISSN: 1432-1912 [Electronic] Germany
• PMID: 21336543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one
• HMGB1 Protein
• Quinolones
• Tumor Necrosis Factor-alpha
• alpha-Defensins
• human neutrophil peptide 1
• human neutrophil peptide 2
• human neutrophil peptide 3
• Kynurenic Acid

Topics

• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• HMGB1 Protein (antagonists & inhibitors, biosynthesis)
• Humans
• Kynurenic Acid (analogs & derivatives, pharmacology)
• Leukocytes, Mononuclear (drug effects, immunology)
• Monocytes (drug effects, immunology)
• Neutrophils (drug effects, immunology)
• Quinolones (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis)
• alpha-Defensins (antagonists & inhibitors, metabolism)