A novel synthetic derivative of melatonin, 5-hydroxy-2 '-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation SCIE SCOPUS

Cited 34 time in WEB OF SCIENCE Cited 34 time in Scopus
Title
A novel synthetic derivative of melatonin, 5-hydroxy-2 '-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation
Author(s)
Shim, Do-Wan; Shin, Hee Jae; Han, Ji-Won; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong; Lee, Kwang-Ho
KIOST Author(s)
Shin, Hee Jae(신희재)
Alternative Author(s)
신희재
Publication Year
2015-04
Abstract
Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (All) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1 beta, IL-6 and TNF-alpha in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of proinflammatory cytokines such as IL-6 and TNF-alpha in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-beta (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1 beta secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1 beta, IL-6 and interferon-beta production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. (C) 2015 Elsevier Inc. All rights reserved.
ISSN
0041-008X
URI
https://sciwatch.kiost.ac.kr/handle/2020.kiost/2503
DOI
10.1016/j.taap.2015.02.006
Bibliographic Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.284, no.2, pp.227 - 235, 2015
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Keywords
Streptochlorin; Melatonin; Anti-inflammation; Inflammasome; Sepsis; ALI
Type
Article
Language
English
Document Type
Article
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Files in This Item:
There are no files associated with this item.

qrcode

Items in ScienceWatch@KIOST are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse