Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

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-κB in these responses, we hypothesized that vesnarinone must modulate NF-κB activation. We investigated the effect of vesnarinone on NF-κB activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-κB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-κB activation in a variety of cells. NF-κB-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-κB activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-κB-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-κB-inducing kinase sites by vesnarinone, thus suppressing NF-κB reporter gene expression. Vesnarinone also blocked NF-κB 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-κB and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone’s ability to suppress inflammation, immunomodulation, and growth regulation.

On the benefits of silymarin in murine colitis by improving balance of destructive cytokines and reduction of toxic stress in the bowel cells

“…Our results show that silymarin is able to reduce TNF-α and IL-1β levels in colonic tissue probably through inhibition of their production or activity. Other investigations confirm such traits for silymarin [26,35]. Inhibition of these major cytokines can lead to the prevention of a detrimental rise in other inflammatory and toxic stress mediators.…”

“…Furthermore, silymarin diminishes the release of proinflammatory cytokines like IL-1, IL-6, interferon (IFN)-γ and TNF-α from activated immune cells and consequently lessens activation of other immune cells following their release [27]. Silymarin is a potent inhibitor of nuclear factor-kappa B (NF-κB) activation, the main mediator of TNF-α effects [35]. Finally, silymarin possesses immunomodulatory [27], anti-angiogenesis [28] and anti-fibrotic functions [29].…”

Role of curcumin and the inhibition of NF-κB in the onset of chemotherapy-induced mucosal barrier injury

“…Curcumin inhibits NF-kB through the suppression of phosphorylation and degradation of IkBa. [42][43][44] CAPE modifies the NF-kB protein so that it can no longer bind to DNA without any effect on IkBa phosphorylation or IkBa degradation. 31,45 Perhaps, by inhibiting the phosphorylation and degradation of IkBa, degradation of other proteins are also inhibited, whereas the inhibition of NFkB binding to DNA could induce apoptosis.…”

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

“…The effect of overexpression of Smad7 on the transcriptional activities of NF-B was investigated further in this doxycyclineregulating Smad7-expressing tubular cell line by transient transfection with an NF-B reporter, 241RMI-SEAP (18). As shown in Figure 9, A and B, doxycycline-induced Smad7 expression significantly inhibited IL-1␤-or TNF-␣-induced NF-B promoter SEAP activities.…”

“…Doxycycline-regulated Smad7-expressing NRK52E cells were transiently transfected by the Lipofectamine (Invitrogen Inc., Carlsbad, CA) with the specific NF-B responsive promoter 241RMI-SEAP (secreted alkaline phosphatase) plasmid (gift from Dr. Bharat B. Aggarwal, Department of Molecular Oncology, University of Texas MD Anderson Cancer Center) (18). A control plasmid, pCMV-␤Gal (Clontech, Palo Alto, CA), was co-transfected into the cells for transfection efficiency.…”