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Infection and Immunity, March 2001, p. 1315-1321, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1315-1321.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibition of Caspase 3 Abrogates Lipopolysaccharide-Induced Nitric Oxide Production by Preventing Activation of NF-kappa B and c-Jun NH2-Terminal Kinase/Stress-Activated Protein Kinase in RAW 264.7 Murine Macrophage Cells

Dipshikha Chakravortty, Yutaka Kato, Tsuyoshi Sugiyama, Naoki Koide, Mya Mya Mu, Tomoaki Yoshida, and Takashi Yokochi*

Department of Microbiology and Immunology and Division of Bacterial Toxin, Research Center for Infectious Disease, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan

Received 11 July 2000/Returned for modification 4 September 2000/Accepted 26 November 2000

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, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), resulted in a striking reduction in LPS-induced NO production. Z-VAD-FMK inhibited LPS-induced NF-kappa B activation. Furthermore, it blocked phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) but not that of extracellular 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-kappa B activation, and JNK/SAPK phosphorylation in LPS-stimulated 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 caspase 3 might abrogate LPS-induced NO production by preventing the activation of NF-kappa B 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.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Aichi 480-1195, Japan. Phone: 81 (561) 62 3311. Fax: 81 (561) 63 9187. E-mail: yokochi{at}amugw.aichi-med-u.ac.jp.

Infection and Immunity, March 2001, p. 1315-1321, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1315-1321.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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