Journal
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Volume 383, Issue 5, Pages 447-455Publisher
SPRINGER
DOI: 10.1007/s00210-011-0605-2
Keywords
Kynurenic acid; TNF-alpha; HMGB1; Defensin-alpha; Monocytes; Granulocytes
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Funding
- Hungarian Research Grant OTKA [K67889/5K540]
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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-alpha (TNF-alpha) 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-alpha, HMGB1 and HNP1-3 concentrations were determined by ELISA, TNF-alpha and HNP1-3 mRNA expressions were quantified by reverse transcription PCR. KynA attenuated the TNF-alpha production of human mononuclear cells activated by heat-inactivated Staphylococcus aureus, inhibiting TNF-alpha 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-alpha, 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.
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