Isopanduratin A Inhibits Tumor Necrosis Factor (TNF)-α-Induced Nuclear Factor κB Signaling Pathway by Promoting Extracellular Signal-Regulated Kinase-Dependent Ectodomain Shedding of TNF Receptor 1 in Human Lung Adenocarcinoma A549 Cells

Yasunobu Miyake,Nghia Trong Vo,Hai Xuan Nguyen,Riho Tanigaki,Chihiro Moriwaki,Takao Kataoka,Truong Nhat Van Do,Nhan Trung Nguyen,Mai Thanh Thi Nguyen

doi:10.3390/biochem1030014

Abstract

Tumor necrosis factor α (TNF-α) induces the nuclear factor κB (NF-κB) signaling pathway via TNF receptor 1 (TNF-R1). We recently reported that isopanduratin A inhibited the TNF-α-induced NF-κB signaling pathway in human lung adenocarcinoma A549 cells. In the present study, we found that isopanduratin A did not inhibit the interleukin-1α-induced NF-κB signaling pathway in A549 cells. Isopanduratin A down-regulated the expression of TNF-R1 in these cells. We also revealed that isopanduratin A down-regulated the cell surface expression of TNF-R1 by promoting the cleavage of TNF-R1 into its soluble forms. TAPI-2, an inhibitor of TNF-α-converting enzyme, suppressed the inhibitory activity of isopanduratin A against the TNF-α-induced activation of NF-κB. The mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not the p38 MAP kinase inhibitor SB203580, blocked the ectodomain shedding of TNF-R1 induced by isopanduratin A. Consistent with this result, isopanduratin A induced the rapid phosphorylation of ERK, but not p38 MAP kinase. Isopanduratin A also promoted the phosphorylation of eukaryotic initiation factor 2α (eIF2α). The present results indicate that isopanduratin A inhibits TNF-α-induced NF-κB signaling pathway by promoting ERK-dependent ectodomain shedding of cell surface TNF-R1, and also decreases cellular TNF-R1 levels through the phosphorylation of eIF2α in A549 cells.

Highlights

Inflammatory cytokines, such as tumor necrosis factor α (TNF-α), are produced by activated macrophages, and stimulate other types of cells to provoke inflammatory responses [1]
To clarify whether isopanduratin A inhibits the converged nuclear factor κB (NF-κB) signaling pathway, A549 cells were pretreated with isopanduratin A, followed by Tumor necrosis factor α (TNF-α) or IL-1α
Isopanduratin A Inhibited inhibitor of NF-κB (IκB) Degradation Induced by TNF-α, but Not IL-1α In NF-κB signaling pathways, TNF-α and IL-1α induce the formation of different membrane-proximal complexes, which converge to activate IκB kinases as the main target [2,3]

Summary

Introduction

Inflammatory cytokines, such as tumor necrosis factor α (TNF-α), are produced by activated macrophages, and stimulate other types of cells to provoke inflammatory responses [1]. TNF-α induces intracellular signaling pathways, one of which leads to the activation of the transcription factor nuclear factor κB (NF-κB) [2,3]. BioChem 2021, 1 complex, which is required for the activation of inhibitor of NF-κB (IκB) kinase [2,3]. IκBα is associated with NF-κB subunits in the cytosol and is rapidly phosphorylated by IκB kinase in response to a TNF-α stimulation, leading to its ubiquitination and degradation by proteasomes [4,5]. NF-κB subunits, typically composed of RelA ( known as p65). The metalloproteinase TNF-α-converting enzyme (TACE) ( known as ADAM17) P50, translocate to the nucleus and activate many of the genes that are essential for inflammatory responses [6,7].

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