Inhibition of lipopolysaccharide-induced pro-inflammatory cytokine expression via suppression of nuclear factor-kappaB activation by Mallotus japonicus phloroglucinol derivatives.
An aqueous acetone extract obtained from the pericarps of Mallotus japonicus (MJE) was observed to inhibit pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production in a lipopolysaccharide (LPS)-activated murine macrophage-like cell line, RAW 264.7, or human blood monocytes. Several phloroglucinol derivatives were isolated from the pericarps as active compounds. Among these compounds, isomallotochromanol and isomallotochromene were the most potent in inhibiting cytokine production. MJE and the phloroglucinol derivatives significantly reduced these cytokine mRNA expressions. Gel shift analysis revealed that stimulation of macrophages with LPS caused an increase in the DNA binding activity of nuclear factor-kappaB (NF-kappaB), which was inhibited by isomallotochromanol and isomallotochromene. Western blot analysis showed that LPS reduced the IkappaB-alpha level in macrophages, while 10 microM isomallotochromanol and 10 microM isomallotochromene attenuated the LPS-induced decrease in IkappaB-alpha protein. We conclude that these phloroglucinol derivatives inhibit pro-inflammatory cytokine production and mRNA expression via suppression of NF-kappaB activation in activated macrophages.
Ishii
Rie
R
Saitama Institute of Public Health, 639-1 Kamiokubo Saitama, Japan.
Horie
Masakazu
M
Saito
Koichi
K
Arisawa
Munehisa
M
Kitanaka
Susumu
S
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D036461:Mallotus Plant / Q000737:chemistry*; D051379:Mice; D009000:Monocytes; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010936:Plant Extracts; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C070199:mallotojaponin; D010696:Phloroglucinol