title: 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.affiliation: Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Tiszlavicz
authors.forename: Balázs
authors.initials: B
authors.lastname: Németh
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
authors.forename: Katalin
authors.initials: K
authors.lastname: Tápai
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszky
authors.forename: Yvette
authors.initials: Y
authors.lastname: Mándi
mesh_terms: D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D015363:Quinolones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D023084:alpha-Defensins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C544943:2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one; D024243:HMGB1 Protein; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2; C406427:human neutrophil peptide 3; D007736:Kynurenic Acid