Abstract.
Objectives:
Heme oxygenase (HO)-1 expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation has an ability to inhibit tumor necrosis factor (TNF)-α 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 (α-methylene-γ-butyrolactone; CH2-BL, α-methyl-γ-butyrolactone; CH3-BL, and γ-butyrolactone; BL) on HO-1 expression as well as TNF-α 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-α 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-α and IL-6. The inhibitory effects of costunolide on TNF-α 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.
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Received 28 January 2007; returned for revision 4 April 2007; returned for final revision 25 June 2007; accepted by A. Falus 14 July 2007
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Pae, HO., Jeong, GS., Kim, HS. et al. Costunolide inhibits production of tumor necrosis factor-α and interleukin-6 by inducing heme oxygenase-1 in RAW264.7 macrophages. Inflamm. res. 56, 520–526 (2007). https://doi.org/10.1007/s00011-007-7015-4
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DOI: https://doi.org/10.1007/s00011-007-7015-4