A synthetic hydroxypropenone inhibits nitric oxide, prostaglandin E2, and proinflammatory cytokine synthesis

Abstract

HMP [3-(2-hydroxyphenyl)-1-(5-methyl-furan-2-y-l) propenone] was evaluated for its ability to inhibit the synthesis of major proinflammatory mediators and cytokines in interferon-γ (IFN-γ)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells and phorbol myristate acetate (PMA)-differentiated/LPS-induced U937 cells. HMP suppressed the production of nitric oxide (NO) with significant inhibitory effects at doses as low as 0.78 μM (P < 0.05). Prostaglandin E2 (PGE2) secretion was also inhibited at doses of 12.5 μM and above (P < 0.01). The secretion of both TNF-α and IL-6 were only inhibited at the highest dose used (25 μM; P < 0.001). IL-1β secretion was also inhibited from 12.5 μM onwards (P < 0.01). This inhibition was demonstrated to be caused by down-regulation of inducible enzymes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), without direct effect upon iNOS or COX-2 enzyme activity. HMP only inhibited iNOS (P < 0.001) and IL-1β (P < 0.05) gene expression at the highest tested concentration. HMP did not affect the secretion of chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) and the anti-inflammatory cytokine IL-10. The most striking effect of HMP was its NO inhibitory activity and therefore we conclude that HMP is a selective inhibitor of iNOS.

Keywords:

• COX-2
• cytokines
• hydroxypropenone
• iNOS
• RAW 264.7
• U937

Acknowledgements

We thank Ms Norazren Ismail and Mr Zulkhairi for technical assistance.

Declaration of interest

This investigation was financially supported by the Research University Grant Scheme (RUGS 04/01/07/0065RU), Universiti Putra Malaysia and Science Fund (02-01-04-SF00665), Ministry of Science, Technology & Innovation, Malaysia.