c-Jun N-terminal kinase attenuates TNFα signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells.

Choi H, Dikalova A, Stark RJ, Lamb FS
Free Radic Biol Med. 2015 86: 219-27

PMID: 26001727 · DOI:10.1016/j.freeradbiomed.2015.05.015

Tumor necrosis factor-α (TNFα), a proinflammatory cytokine, causes vascular smooth muscle cell (VSMC) proliferation and migration and promotes inflammatory vascular lesions. Nuclear factor-kappa B (NF-κB) activation by TNFα requires endosomal superoxide production by Nox1. In endothelial cells, TNFα stimulates c-Jun N-terminal kinase (JNK), which inhibits NF-κB signaling. The mechanism by which JNK negatively regulates TNFα-induced NF-κB activation has not been defined. We hypothesized that JNK modulates NF-κB activation in VSMC, and does so via a Nox1-dependent mechanism. TNFα-induced NF-κB activation was TNFR1- and endocytosis-dependent. Inhibition of endocytosis with dominant-negative dynamin (DynK44A) potentiated TNFα-induced JNK activation, but decreased ERK activation, while p38 kinase phosphorylation was not altered. DynK44A attenuated intracellular, endosomal superoxide production in wild-type (WT) VSMC, but not in NADPH oxidase 1 (Nox1) knockout (KO) cells. siRNA targeting JNK1 or JNK2 potentiated, while a JNK activator (anisomycin) inhibited, TNFα-induced NF-κB activation in WT, but not in Nox1 KO cells. TNFα-stimulated superoxide generation was enhanced by JNK1 inhibition in WT, but not in Nox1 KO VSMC. These data suggest that JNK suppresses the inflammatory response to TNFα by reducing Nox1-dependent endosomal ROS production. JNK and endosomal superoxide may represent novel targets for pharmacologic modulation of TNFα signaling and vascular inflammation.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (18)

Animals Cells, Cultured Endocytosis Endosomes JNK Mitogen-Activated Protein Kinases Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases Muscle, Smooth, Vascular Myocytes, Smooth Muscle NADH, NADPH Oxidoreductases NADPH Oxidase 1 NF-kappa B Reactive Oxygen Species Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Signal Transduction Tumor Necrosis Factor-alpha

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