Sulforaphane and its methylcarbonyl analogs inhibit the LPS-stimulated inflammatory response in human monocytes through modulating cytokine production, suppressing chemotactic migration and phagocytosis in a NF-κB- and MAPK-dependent manner

Int Immunopharmacol. 2015 Feb;24(2):440-450. doi: 10.1016/j.intimp.2014.12.037. Epub 2015 Jan 10.

Abstract

Sulforaphane [SF; 1-isothiocyanato-4-(methylsulfinyl)-butane], an aliphatic isothiocyanate (ITC) naturally derived from cruciferous vegetables and largely known for its chemopreventive potential also appears to possess anti-inflammatory potential. In this study, structural analogs of SF {compound 1 [1-isothiocyanato-4-(methylcarbonyl)-butane] and 2 [1-isothiocyanato-3-(methylcarbonyl)-propane]} containing a carbonyl group in place of the sulfinyl group in SF, were evaluated for their anti-inflammatory activities. In RAW 264.7 cells, the ITCs at non-toxic concentrations caused an inhibition of NO and prostaglandin E2 (PGE2) release through suppressing expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as a reduction in matrix metalloproteinase-9 (MMP-9) expression, secretion and gelatinolytic activity. Further work performed on human monocytes isolated from blood of healthy donors revealed that the ITCs not only suppressed the expression and release of pro-inflammatory mediators IL-1β, IL-6, TNF-α and MMP-9, but also suppressed their antibody-independent phagocytic and chemotactic migratory abilities. These anti-inflammatory activities were mediated through suppression of the NF-κB and MAPK signaling pathways. In addition, the ITCs were revealed to interact with the cysteines in inhibitor of nuclear factor-κB kinase β subunit (IKKβ), which could contribute at least partly to the suppression of NF-κB signaling. In conclusion, results obtained in this study provide deeper insights into the anti-inflammatory properties of SF and its methylcarbonyl analogs and the underlying mechanisms. These compounds thus serve as promising candidates for clinical applications in controlling inflammatory conditions.

Keywords: Human monocytes; Inflammation; Isothiocyanates; MAPK; NF-κB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Line
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dinoprostone / metabolism
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • Isothiocyanates / pharmacology*
  • Lipopolysaccharides
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Monocytes / physiology
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Nitrites / metabolism
  • Phagocytosis / drug effects
  • Sulfoxides

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Isothiocyanates
  • Lipopolysaccharides
  • NF-kappa B
  • Nitrites
  • Sulfoxides
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • I-kappa B Kinase
  • Mitogen-Activated Protein Kinases
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • sulforaphane
  • Dinoprostone