Sappanone A exhibits anti-inflammatory effects via modulation of Nrf2 and NF-κB

Int Immunopharmacol. 2015 Sep;28(1):328-36. doi: 10.1016/j.intimp.2015.06.015. Epub 2015 Jun 26.

Abstract

Homoisoflavonoids constitute a small class of natural products. In the present study, we investigated the anti-inflammatory effect of sappanone A (SPNA), a homoisoflavanone that is isolated from the heartwood of Caesalpinia sappan (Leguminosae), in murine macrophages. SPNA inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-6 (IL-6) as well as the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, SPNA protected C57BL/6 mice from LPS-induced mortality. Treatment of RAW264.7 cells with SPNA induced heme oxygenase (HO)-1 protein and mRNA expression and increased nuclear translocation of the nuclear factor-E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes such as

Nad(p)h: quinone oxidoreductase 1 (NQO1). Knockdown of Nrf2 by siRNA blocked SPNA-mediated HO-1 induction. SB203580, p38 mitogen-activated protein kinase (MAPK) inhibitor, blocked SPNA-induced HO-1 expression and nuclear translocation of Nrf2, suggesting that SPNA induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti-inflammatory properties, inhibiting HO-1 significantly abrogated the anti-inflammatory effects of SPNA in LPS-stimulated RAW264.7 cells. Moreover, SPNA suppressed LPS-induced nuclear factor κB (NF-κB) activation via inhibiting Ser 536 phosphorylation and transcriptional activity of RelA/p65 subunit of NF-κB. Taken together, these findings suggest that SPNA exerts its anti-inflammatory effect by modulating the Nrf2 and NF-κB pathways, and may be a valuable compound to prevent or treat inflammatory diseases.

Keywords: Anti-inflammation; Heme oxygenase-1; Homoisoflavonoids; NF-κB; Nrf2; Sappanone A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Caesalpinia
  • Cell Line
  • Dinoprostone / metabolism
  • Heme Oxygenase-1 / metabolism
  • Interleukin-6 / metabolism
  • Isoflavones / pharmacology*
  • Lipopolysaccharides
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism*
  • Nitric Oxide / metabolism
  • Wood

Substances

  • Anti-Inflammatory Agents
  • Interleukin-6
  • Isoflavones
  • Lipopolysaccharides
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NF-kappa B
  • interleukin-6, mouse
  • sappanone A
  • Nitric Oxide
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Dinoprostone