CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency

Pamela S. Cohen, Harikrishna Nakshatri, Jameel Dennis, Theresa Caragine, Marina Bianchi, Anthony Cerami, Kevin J. Tracey

Research output: Contribution to journalArticle

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Abstract

Tumor necrosis factor (TNF) mediates a wide variety of disease states including septic shock, acute and chronic inflammation, and cachexia. Recently, a multivalent guanylhydrazone (CNI-1493) developed as an inhibitor of macrophage activation was shown to suppress TNF production and protect against tissue inflammation and endotoxin lethality [Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G. A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B., Manogue, K. R., Tortolani, A. J., Cerami, A. and Tracey, K. J. (1995) Mol. Med. 1, 254-266, and Bianchi, M., Bloom, O., Raabe, T., Cohen, P. S., Chesney, J., Sherry, B., Schmidtmayerova, H., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A. and Tracey, J. (1996) J. Exp. Med., in press]. We have now elucidated the mechanism by which CNI-1493 inhibits macrophage TNF synthesis and show here that it acts through suppression of TNF translation efficiency. CNI-1493 blocked neither the lipopolysaccharide (LPS)-induced increases in the expression of TNF mRNA nor the translocation of nuclear factor NF-κB to the nucleus in macrophages activated by 15 min of LPS stimulation, indicating that CNI-1493 does not interfere with early NF-κB-mediated transcriptional regulation of TNF. However, synthesis of the 26-kDa membrane form of TNF was effectively blocked by CNI-1493. Further evidence for the translational suppression of TNF is given by experiments using chloramphenicol acetyltransferase (CAT) constructs containing elements of the TNF gene that are involved in TNF translational regulation. Both the 5' and 3' untranslated regions of the TNF gene were required to elicit maximal translational suppression by CNI-1493. Identification of the molecular target through which CNI-1493 inhibits TNF translation should provide insight into the regulation of macrophage activation and mechanisms of inflammation.

Original languageEnglish (US)
Pages (from-to)3967-3971
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number9
DOIs
StatePublished - Apr 30 1996
Externally publishedYes

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Monocytes
Tumor Necrosis Factor-alpha
Macrophages
Macrophage Activation
Inflammation
Lipopolysaccharides
semapimod
Cachexia
Chloramphenicol O-Acetyltransferase
5' Untranslated Regions
3' Untranslated Regions
Septic Shock
Endotoxins
Genes
Messenger RNA
Membranes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. / Cohen, Pamela S.; Nakshatri, Harikrishna; Dennis, Jameel; Caragine, Theresa; Bianchi, Marina; Cerami, Anthony; Tracey, Kevin J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 9, 30.04.1996, p. 3967-3971.

Research output: Contribution to journalArticle

Cohen, Pamela S. ; Nakshatri, Harikrishna ; Dennis, Jameel ; Caragine, Theresa ; Bianchi, Marina ; Cerami, Anthony ; Tracey, Kevin J. / CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 9. pp. 3967-3971.
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AU - Nakshatri, Harikrishna

AU - Dennis, Jameel

AU - Caragine, Theresa

AU - Bianchi, Marina

AU - Cerami, Anthony

AU - Tracey, Kevin J.

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