A synthetic hydroxypropenone inhibits nitric oxide, prostaglandin E2, and proinflammatory cytokine synthesis.
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-gamma (IFN-gamma)- 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 microM (P < 0.05). Prostaglandin E2 (PGE2) secretion was also inhibited at doses of 12.5 microM and above (P < 0.01). The secretion of both TNF-alpha and IL-6 were only inhibited at the highest dose used (25 microM; P < 0.001). IL-1beta secretion was also inhibited from 12.5 microM 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-1beta (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.
Liew
Choi Yi
CY
Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
Tham
Chau Ling
CL
Lam
Kok Wai
KW
Mohamad
Azam Shah
AS
Kim
Min Kyu
MK
Cheah
Yoke Kqueen
YK
Zakaria
Zainul Amiruddin
ZA
Sulaiman
Mohd Roslan
MR
Lajis
Md Nordin
MN
Israf
Daud Ahmad
DA
D000818:Animals; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020298:U937 Cells; D000093242:Interleukin-6 Inhibitors
D047188:Chalcones; D051546:Cyclooxygenase 2; D016207:Cytokines; D015232:Dinoprostone; D005663:Furans; D016898:Interferon-alpha; D007371:Interferon-gamma; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011427:Propiophenones; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C553916:3-(2-hydroxyphenyl)-1-(5-methylfuran-2-yl)propenone