TNF-α promotes cell survival through stimulation of K+ channel and NFκB activity in corneal epithelial cells

Abstract

Tumor necrosis factor (TNF-α) in various cell types induces either cell death or mitogenesis through different signaling pathways. In the present study, we determined in human corneal epithelial cells how TNF-α also promotes cell survival. Human corneal epithelial (HCE) cells were cultured in DMEM/F-12 medium containing 10% FBS. TNF-α stimulation induced activation of a voltage-gated K + channel detected by measuring single channel activity using patch clamp techniques. The effect of TNF-α on downstream events included NFκB nuclear translocation and increases in DNA binding activities, but did not elicit ERK, JNK, or p38 limb signaling activation. TNF-α induced increases in p21 expression resulting in partial cell cycle attenuation in the G 1 phase. Cell cycle progression was also mapped by flow cytometer analysis. Blockade of TNF-α-induced K + channel activity effectively prevented NFκB nuclear translocation and binding to DNA, diminishing the cell-survival protective effect of TNF-α. In conclusion, TNF-α promotes survival of HCE cells through sequential stimulation of K + channel and NFκB activities. This response to TNF-α is dependent on stimulating K + channel activity because following suppression of K + channel activity TNF-α failed to activate NFκB nuclear translocation and binding to nuclear DNA.

Musca domestica Pupae Lectin Improves the Immunomodulatory Activity of Macrophages by Activating Nuclear Factor-κB

“…38 It has been reported that TNF-a can promote cell survival through stimulation of NF-jB activity in corneal epithelial cells. 39 As one of the most important endogenous mediators of immunity and inflammation, IFN-c plays a critical role in normal immune functions, including macrophage activation, inflammation, host defense against intracellular pathogens, etc. 40 Not only the mRNA expressions, but also the protein secretions, of IL-6, TNF-a, and INF-c in macrophages treated by MPL were up-regulated.…”

NF-κB Subtypes Regulate CCCTC Binding Factor Affecting Corneal Epithelial Cell Fate

“…Tumor necrosis factor-␣ does not induce corneal epithelial cell apoptosis, but instead increases expression of p21 and cell cycle attenuation in the G 1 phase. This in turn promotes cell survival (32). However, the functional role of NF-B in regulating corneal epithelial cell proliferation and apoptosis is largely undefined.…”

“…Inflammation induces immune responses and stimulates production of pro-inflammatory cytokine/chemokines (tumor necrosis factor-␣ and interleukins 1, 6, and 8), which leads to activation of the mitogen-activated protein kinase cascades, such as ERK, c-Jun N-terminal kinase (JNK), and p38 signal pathways (6, 11, 30 -33). The downstream effect includes NF-B phosphorylation and subsequent translocation to the nucleus (30,32,34). There are five NF-B subtypes in mammalian cells, including RelA (p65), RelB, c-Rel, NF-B1 (p50), and NF-B2 (p52).…”

The corneal epithelium: clinical relevance of cytokine-mediated responses to maintenance of corneal health

“…One cytokine that is protective against cell loss through apoptosis is neural growth factor (NGF) (40) , while pro-inflammatory cytokines, i.e., tumor necrosis factor (TNF)α, act to promote apoptosis (41) . On the other hand, in vitro TNFα supports human corneal epithelial cell survival (42) .…”