Inhibition of caspase 3 abrogates lipopolysaccharide-induced nitric oxide production by preventing activation of NF-κB and c-jun NH2-terminal kinase/stress-activated protein kinase in RAW 264.7 murine macrophage cells

D. Chakravortty, Y. Kato, T. Sugiyama, N. Koide, Mya Mu Mya Mya Mu, T. Yoshida, T. Yokochi

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The effect of caspase inhibitors on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 267.4 murine macrophage cells was investigated. Pretreatment of RAW cells with a broad caspase inhibitor, benzyioxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), resulted in a striking reduction in LPS-induced NO production. Z-VAD-FMK inhibited LPS-induced NF-κB activation. Furthermore, it blocked phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) but not that of extraeellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases. Similarly, a caspase 3-specific inhibitor, Z-Asp-Glu-Val-Asp-fluoromethylketone, inhibited NO production, NF-κB activation, and JNK/SAPK phosphorylation in LPS-stimutated RAW cells. The attenuated NO production was due to inhibition of the expression of an inducible-type NO synthase (iNOS). The overexpression of the dominant negative mutant of JNK/SAPK and the addition of a JNK/SAPK inhibitor blocked iNOS expression but did not block LPS-induced caspase 3 activation. It was therefore suggested that the inhibition of easpase 3 might abrogate LPS-induced NO production by preventing the activation of NF-KB and JNK/SAPK. The caspase family, especially caspase 3, is likely to play an important role in the signal transduction for iNOS-mediated NO production in LPS-stimulated mouse macrophages.

Original languageEnglish
Pages (from-to)1315-1321
Number of pages7
JournalInfection and Immunity
Volume69
Issue number3
DOIs
Publication statusPublished - 14-03-2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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