Activation of Potassium and Chloride Channels by Tumor Necrosis Factor α

Abstract

Despite abundant evidence for changes in mitochondrial membrane permeability in tumor necrosis factor (TNF)-mediated cell death, the role of plasma membrane ion channels in this process remains unclear. These studies examine the influence of TNF on ion channel opening and death in a model rat liver cell line (HTC). TNF (25 ng/ml) elicited a 2-and 5-fold increase in K ؉ and Cl ؊ currents, respectively, in HTC cells. These increases occurred within 5-10 min after TNF exposure and were inhibited either by K ؉ or Cl ؊ substitution or by K ؉ channel blockers (Ba 2؉ , quinine, 0.1 mM each) or Cl ؊ channel blockers (10 M 5-nitro-2-(3-phenylpropylamino)benzoic acid and 0.1 mM N-phenylanthranilic acid), respectively. TNF-mediated increases in K ؉ and Cl ؊ currents were each inhibited by intracellular Ca 2؉ chelation (5 mM EGTA), ATP depletion (4 units/ml apyrase), and the protein kinase C (PKC) inhibitors chelerythrine (10 M) or PKC 19 -36 peptide (1 M). In contrast, currents were not attenuated by the calmodulin kinase II 281-309 peptide (10 M), an inhibitor of calmodulin kinase II. In the presence of actinomycin D (1 M), each of the above ion channel blockers significantly delayed the progression to TNF-mediated cell death. Collectively, these data suggest that activation of K ؉ and Cl ؊ channels is an early response to TNF signaling and that channel opening is Ca 2؉ -and PKC-dependent. Our findings further suggest that K ؉ and Cl ؊ channels participate in pathways leading to TNF-mediated cell death and thus represent potential therapeutic targets to attenuate liver injury from TNF.

Regulation of Intracellular pH Mediates Bax Activation in HeLa Cells Treated with Staurosporine or Tumor Necrosis Factor-α

“…Ceramide is known to signal TNF by activation of kinase cascades, as well as by a ceramide-activated protein phosphatase. In this regard, TNF is reported to activate K ϩ and Cl Ϫ channels in a variety of cells, including neutrophils, neurons, and hepatoma cells (36).…”

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

“…TNF-α is secreted by corneal epithelial cells in response to an inflammatory stimulation caused by bacterial and viral infections (Minami et al, 2002;Kurpakus-Wheater et al, 2003;Bitko et al, 2004;Kumar et al, 2004). TNF-α-stimulated increases in K + channel activities are important for TNF-α-induced cellular effects in cortical neurons, kidney epithelial cells, hepatic cells and corneal epithelial cells (Houzen et al, 1997;Nietsch et al, 2000;Wei et al, 2003). TNF-α also induces mRNA expression of various K + channel types during a systemic inflammatory response as well as tumor cell proliferation in brain and cancer cells Vicente et al, 2003Vicente et al, ,2004.…”

A role of reactive oxygen species in apoptotic activation of volume-sensitive Cl-channel

“…The apoptotic volume decrease (AVD) is an early-phase, essential component of the cascade leading to apoptotic cell death and is driven by osmolyte efflux resulting mainly from activation of K ϩ and Cl Ϫ conductances (1,2). Actually, several studies have reported that Cl Ϫ currents are activated on apoptotic stimulation (3)(4)(5)(6), although little is known concerning the type of Cl Ϫ channel and its activating signal. The involvement of the volume-sensitive outwardly rectifying (VSOR) Cl Ϫ channel has been suggested on the basis of observations that induction of AVD is coupled to a facilitation of the regulatory volume decrease (RVD) and prevented by known blockers of VSOR but not of cAMP-and Ca 2ϩ -activated Cl Ϫ channels (7).…”