Anti-inflammatory effect of caffeic acid methyl ester and its mode of action through the inhibition of prostaglandin E2, nitric oxide and tumor necrosis factor-alpha production.
The anti-inflammatory effects of caffeic acid (CA), caffeic acid methyl ester (CM) and di-O-acetylcaffeic acid (DAC) were investigated in rats using the carrageenin-induced edema model and the antinociceptive effects of these compounds were also assessed in mice by means of the acetic acid-induced abdominal constriction test and hot plate test. CM (10mg/kg, p.o.) showed the most potent anti-inflammatory and antinociceptive effects in these animal models. To investigate the mechanism of the anti-inflammatory action, we examined the effects of these compounds on the lipopolysaccharide (LPS)-induced NO and PGE2 responses in the murine macrophage cell line, RAW 264.7. Our data indicate that CM is the most potent inhibitor of NO and PGE2 production and it also significantly decreased tumor necrosis factor-alpha (TNF-alpha) release. Consistent with these observations, the protein and mRNA expression levels of iNOS and COX-2 were found to be inhibited by CM in a dose-dependent manner. Furthermore, CM inhibited the nuclear factor-kappaB (NF-kappaB) activation induced by LPS, which was associated with the prevention of the degradation of the inhibitor kappaB, and subsequently with decreased p65 protein levels in the nucleus. Taken together, our data indicate that the anti-inflammatory properties of CM might result from the inhibition of iNOS, COX-2 and TNF-alpha expression through the down-regulation of NF-kappaB binding activity.
Shin
Kyung-Min
KM
College of Pharmacy, Kyung-Hee University, Dongdaemun-ku, Hoegi-Dong, Seoul 130-701, South Korea.
Kim
In-Tae
IT
Park
Young-Mi
YM
Ha
Joohun
J
Choi
Jong-Won
JW
Park
Hee-Juhn
HJ
Lee
Yong Sup
YS
Lee
Kyung-Tae
KT
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004952:Esters / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D011458:Prostaglandins E / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D002109:Caffeic Acids; D002352:Carrier Proteins; D004952:Esters; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009363:Neoplasm Proteins; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D029543:Nucleocytoplasmic Transport Proteins; D011458:Prostaglandins E; D012333:RNA, Messenger; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C497946:di-O-acetylcaffeic acid; C063447:p65 oncofetal mRNA transport protein, rat; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C497945:caffeic acid methyl ester; C040048:caffeic acid