Tags

Type your tag names separated by a space and hit enter

Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis.
J Immunol. 2000 Jun 01; 164(11):5815-25.JI

Abstract

Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-kappa B in these responses, we hypothesized that vesnarinone must modulate NF-kappa B activation. We investigated the effect of vesnarinone on NF-kappa B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-kappa B activation in a variety of cells. NF-kappa B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-kappa B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-kappa B-inducing kinase sites by vesnarinone, thus suppressing NF-kappa B reporter gene expression. Vesnarinone also blocked NF-kappa B activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-kappa B and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone's ability to suppress inflammation, immunomodulation, and growth regulation.

Authors+Show Affiliations

Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10820260

Citation

Manna, S K., and B B. Aggarwal. "Vesnarinone Suppresses TNF-induced Activation of NF-kappa B, c-Jun Kinase, and Apoptosis." Journal of Immunology (Baltimore, Md. : 1950), vol. 164, no. 11, 2000, pp. 5815-25.
Manna SK, Aggarwal BB. Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. J Immunol. 2000;164(11):5815-25.
Manna, S. K., & Aggarwal, B. B. (2000). Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. Journal of Immunology (Baltimore, Md. : 1950), 164(11), 5815-25.
Manna SK, Aggarwal BB. Vesnarinone Suppresses TNF-induced Activation of NF-kappa B, c-Jun Kinase, and Apoptosis. J Immunol. 2000 Jun 1;164(11):5815-25. PubMed PMID: 10820260.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. AU - Manna,S K, AU - Aggarwal,B B, PY - 2000/5/23/pubmed PY - 2000/6/24/medline PY - 2000/5/23/entrez SP - 5815 EP - 25 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 164 IS - 11 N2 - Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-kappa B in these responses, we hypothesized that vesnarinone must modulate NF-kappa B activation. We investigated the effect of vesnarinone on NF-kappa B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-kappa B activation in a variety of cells. NF-kappa B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-kappa B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-kappa B-inducing kinase sites by vesnarinone, thus suppressing NF-kappa B reporter gene expression. Vesnarinone also blocked NF-kappa B activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-kappa B and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone's ability to suppress inflammation, immunomodulation, and growth regulation. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/10820260/Vesnarinone_suppresses_TNF_induced_activation_of_NF_kappa_B_c_Jun_kinase_and_apoptosis_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=10820260 DB - PRIME DP - Unbound Medicine ER -