Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro

M. Zinetti, G. Galli, M. T. Demitri, G. Fantuzzi, M. Minto, P. Ghezzi, R. Alzani, E. Cozzi, M. Fratelli

Research output: Contribution to journalArticle

Abstract

Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysaccharide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-α (TNF-α) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-α action by assessing TNF-α cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1-100 μM) inhibited TNF-α production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclic AMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10-25 μM) also inhibited TNF-α activity: in fact it reduced the cytotoxicity of TNF-α on L929 cells (EC50 was increased four times) and could provide protection even as a post-treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-α or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-α signalling pathways.

Original languageEnglish
Pages (from-to)416-421
Number of pages6
JournalImmunology
Volume86
Issue number3
Publication statusPublished - 1995

ASJC Scopus subject areas

  • Immunology

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    Zinetti, M., Galli, G., Demitri, M. T., Fantuzzi, G., Minto, M., Ghezzi, P., Alzani, R., Cozzi, E., & Fratelli, M. (1995). Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro. Immunology, 86(3), 416-421.