Costunolide inhibits production of tumor necrosis factor-alpha and interleukin-6 by inducing heme oxygenase-1 in RAW264.7 macrophages.
OBJECTIVE
Heme oxygenase (HO)-1 expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation has an ability to inhibit tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. Costunolide has been reported to inhibit IL-1 production, but whether other cytokines could be inhibited remains to be confirmed. We investigated the effects of costunolide and its components (alpha-methylene-gamma-butyrolactone; CH2-BL, alpha-methyl-gamma-butyrolactone; CH3-BL, and gamma-butyrolactone; BL) on HO-1 expression as well as TNF-alpha and IL-6 production in RAW264.7 macrophages.


METHODS
HO-1 expression and Nrf2 nuclear accumulation were analyzed by Western blot analysis. The production of TNF-alpha and IL-6 in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) was assayed by ELISA.


RESULTS
Costunolide and CH2-BL induced HO-1 expression and Nrf2 nuclear accumulation, whereas CH3-BL and BL did not. Pre-incubation with costunolide inhibited LPS-induced production of TNF-alpha and IL-6. The inhibitory effects of costunolide on TNF-alpha and IL-6 production were abrogated by tin protoporphyrin, an HO inhibitor.


CONCLUSIONS
Costunolide is an effective HO-1 inducer capable of inhibiting macrophage-derived pro-inflammatory cytokines. CH2-BL moiety of costunolide is essential for Nrf2 activation leading to HO-1 expression.
Pae
H-O
HO
Medicinal Resources Research Institute, Wonkwang University, Iksan, Chonbug, Republic of Korea.
Jeong
G-S
GS
Kim
H-S
HS
Woo
W H
WH
Rhew
H Y
HY
Kim
H S
HS
Sohn
D H
DH
Kim
Y-C
YC
Chung
H-T
HT
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors; D007783:Lactones
D015107:4-Butyrolactone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051547:Heme Oxygenase-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D011524:Protoporphyrins; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C495636:Nfe2l2 protein, mouse; C014096:alpha-methylene gamma-butyrolactone; C002602:costunolide; D007783:Lactones