Anti-inflammatory subtilase cytotoxin up-regulates A20 through the unfolded protein response

We recently reported that subtilase cytotoxin (SubAB) has the potential to attenuate experimental models of inflammatory diseases [3]. Currently, little is known about underlying mechanisms involved in this therapeutic effect. In the present report, we show that SubAB induces A20, the endogenous neg...

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Published in:Biochemical and biophysical research communications 2010-06, Vol.397 (2), p.176-180
Main Authors: Nakajima, Shotaro, Saito, Yukinori, Takahashi, Shuhei, Hiramatsu, Nobuhiko, Kato, Hironori, Johno, Hisashi, Yao, Jian, Paton, Adrienne W., Paton, James C., Kitamura, Masanori
Format: Article
Language:English
Subjects:
A20
Animals
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Cell Line
DNA-Binding Proteins - biosynthesis
Escherichia coli Proteins - pharmacology
Inflammation - enzymology
NF-kappa B - metabolism
NF-κB
Rats
Subtilase cytotoxin
Subtilisins - pharmacology
Ubiquitin-Protein Ligases - biosynthesis
Unfolded Protein Response
Up-Regulation
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Summary:We recently reported that subtilase cytotoxin (SubAB) has the potential to attenuate experimental models of inflammatory diseases [3]. Currently, little is known about underlying mechanisms involved in this therapeutic effect. In the present report, we show that SubAB induces A20, the endogenous negative regulator of NF-κB, in vitro and in vivo. This stimulatory effect occurred at the transcriptional level, and SubAB induced activation of the A20 promoter. We found that, in the early phase, SubAB triggered activation of NF-κB in a dose-dependent manner. Blockade of NF-κB abrogated expression of A20 by SubAB. SubAB rapidly triggered the unfolded protein response (UPR), and induction of the UPR by other agents (thapsigargin and A23187) mimicked the stimulatory effects of SubAB, both on NF-κB and on A20. The induction of A20 by thapsigargin was correlated with activation of the A20 promoter, which was not observed in the κB-mutated A20 promoter. Furthermore, induction of A20 by SubAB was substantially attenuated by treatment with different chemical chaperones. These results elucidated for the first time that the anti-inflammatory SubAB has the potential to induce A20 through the UPR–NF-κB-dependent pathway.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2010.05.069