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.
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.