NDLI: Pleiotropic potential of dehydroxymethylepoxyquinomicin for NF-κB suppression via reactive oxygen species and unfolded protein response.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Johno, Hisashi Gu, Liubao Takahashi, Shuhei Kitamura, Masanori Nakajima, Shotaro Kato, Hironori Umezawa, Kazuo
Description	Country affiliation: Japan Author Affiliation: Nakajima S ( Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.)
Abstract	Dehydroxymethylepoxyquinomicin (DHMEQ) is a low-m.w. compound that strongly inhibits NF-κB. Previous reports showed that DHMEQ directly binds to specific cysteine residues of NF-κB subunits and thereby inhibits their nuclear translocation and DNA binding. In this work, we describe novel mechanisms by which DHMEQ suppresses cytokine-triggered activation of NF-κB. We found that sustained exposure of renal tubular cells to DHMEQ blocked TNF- - and IL-1ß-induced TGF-ß-activated kinase 1 (TAK1) phosphorylation, a crucial event for NF-κB activation upstream of IκB kinase. This inhibition was mediated by reactive oxygen species (ROS), because of the following: 1) DHMEQ caused generation of ROS; 2) pretreatment with ROS generator inhibited cytokine-induced TAK1 phosphorylation and NF-κB activation; and 3) scavenging of ROS attenuated the suppressive effects of DHMEQ on TAK1 and NF-κB. We also found that DHMEQ caused the unfolded protein response (UPR) through generation of ROS. Alleviation of the UPR by chemical and genetic chaperones partially attenuated the suppressive effect of DHMEQ on NF-κB. The UPR-mediated inhibition of NF-κB occurred downstream of degradation of IκB and phosphorylation of p65. Subsequent experiments revealed the following: 1) DHMEQ caused selective induction of C/EBPß through the UPR; 2) overexpression of C/EBPß suppressed activation of NF-κB; 3) knockdown of C/EBPß attenuated the inhibitory effect of DHMEQ; and 4) DHMEQ-induced expression of C/EBPß did not affect TNF- -triggered degradation of IκB and phosphorylation of p65. These results suggest that, in addition to its known effect on nuclear translocation of NF-κB, DHMEQ interferes with the cytokine-induced NF-κB signaling via generation of ROS at both upstream and downstream of the IκB kinase-IκB level.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	12
Volume Number	190
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-06-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Benzamides Pharmacology Cyclohexanones Nf-kappa B Metabolism Reactive Oxygen Species Signal Transduction Drug Effects Unfolded Protein Response Animals Blotting, Northern Blotting, Western Hek293 Cells Immunoprecipitation Mice Mice, Inbred C57bl Transfection Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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