6-(Methylsulfinyl)hexyl isothiocyanate suppresses inducible nitric oxide synthase expression through the inhibition of Janus kinase 2-mediated JNK pathway in lipopolysaccharide-activated murine macrophages

Biochem Pharmacol. 2005 Oct 15;70(8):1211-21. doi: 10.1016/j.bcp.2005.07.011.


6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC) is an active ingredient of Wasabi (Wasabia japonica (Miq.) Matsumura), which is a very popular pungent spice in Japan. To clarify the cellular signaling mechanism underlying the anti-inflammatory action of 6-MITC, we investigated the effects of 6-MITC on the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. 6-MITC showed a dose-dependent inhibition of LPS-induced nitric oxide (NO), iNOS mRNA and protein. LPS caused the c-Jun phosphorylation (a major component of AP-1) and IkappaB-alpha degradation. 6-MITC suppressed LPS-induced c-Jun phosphorylation, but did not inhibit IkappaB-alpha degradation. Cellular signaling analysis using MAPK-(U0126 for MEK1/2, SB203580 for p38 kinase and SP600125 for JNK) and Jak2-specific (AG490) inhibitors demonstrated that LPS stimulated iNOS expression via activating Jak2-mediated JNK, but not ERK and p38, pathway. 6-MITC suppressed iNOS expression through the inhibition of Jak2-mediated JNK signaling cascade with the attendant to AP-1 activation. In addition, the structure-activity study revealed that the inhibitory potency of methylsulfinyl isothiocyanates (MITCs) depended on the methyl chain length. These findings provide the molecular basis for the first time that 6-MITC is an effective agent to attenuate iNOS production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Primers
  • Enzyme Inhibitors / pharmacology*
  • Isothiocyanates / pharmacology*
  • Janus Kinase 2
  • Lipopolysaccharides / pharmacology*
  • Macrophage Activation
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Mice
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics


  • 6-(Methylsulfinyl)hexyl isothiocyanate
  • DNA Primers
  • Enzyme Inhibitors
  • Isothiocyanates
  • Lipopolysaccharides
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2