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Title: LYATK1 potently inhibits LPS-mediated pro-inflammatory response

Abstract

Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than othermore » known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.« less

Authors:
 [1];  [2]; ;  [1];  [1]
  1. Department of Intensive Care Unit, Taixing People"'s Hospital, Taixing, Jiangsu Province, 225400 (China)
  2. Department of Ophthalmology, Nanjing First Hospital, Nanjing Medical University, Nanjing (China)
Publication Date:
OSTI Identifier:
22594204
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 470; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BONE MARROW; ENDOTOXINS; IN VITRO; IN VIVO; INFLAMMATION; LIPOPOLYSACCHARIDES; LYMPHOKINES; MACROPHAGES; MESSENGER-RNA; MICE; MONOCYTES; NECROSIS; NEOPLASMS; RADIOPROTECTIVE SUBSTANCES; SKELETON

Citation Formats

Xi, Feng, Liu, Yuan, Wang, Xiujuan, Kong, Wei, and Zhao, Feng, E-mail: taixingzhaofeng163@163.com. LYATK1 potently inhibits LPS-mediated pro-inflammatory response. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2015.11.090.
Xi, Feng, Liu, Yuan, Wang, Xiujuan, Kong, Wei, & Zhao, Feng, E-mail: taixingzhaofeng163@163.com. LYATK1 potently inhibits LPS-mediated pro-inflammatory response. United States. doi:10.1016/J.BBRC.2015.11.090.
Xi, Feng, Liu, Yuan, Wang, Xiujuan, Kong, Wei, and Zhao, Feng, E-mail: taixingzhaofeng163@163.com. Fri . "LYATK1 potently inhibits LPS-mediated pro-inflammatory response". United States. doi:10.1016/J.BBRC.2015.11.090.
@article{osti_22594204,
title = {LYATK1 potently inhibits LPS-mediated pro-inflammatory response},
author = {Xi, Feng and Liu, Yuan and Wang, Xiujuan and Kong, Wei and Zhao, Feng, E-mail: taixingzhaofeng163@163.com},
abstractNote = {Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.},
doi = {10.1016/J.BBRC.2015.11.090},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 470,
place = {United States},
year = {Fri Jan 29 00:00:00 EST 2016},
month = {Fri Jan 29 00:00:00 EST 2016}
}