The IRAK-ERK-p67phox-Nox-2 axis mediates TLR4, 2-induced ROS production for IL-lp transcription and processing in monocytes

In monocytic cells, Toll-like receptor 4 （TLR4）- and TLR2-induced reactive oxygen species （ROS） cause oxidative stress and inflammatory response; however, the mechanism is not well understood. The present study investigated the role of interleukin-1 receptor-associated kinase （IRAK）, extracellular s...

Full description

Saved in:
Bibliographic Details
Published in:中国免疫学杂志：英文版 2016, Vol.13 (6), p.747-763
Main Author: Ankita Singh Vishal Singh Rajiv L. Tiwari Tulika Chandra Ashutosh Kumar Madhu Dikshit Manoj K. Barthwal
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In monocytic cells, Toll-like receptor 4 （TLR4）- and TLR2-induced reactive oxygen species （ROS） cause oxidative stress and inflammatory response; however, the mechanism is not well understood. The present study investigated the role of interleukin-1 receptor-associated kinase （IRAK）, extracellular signal-regulated kinase （ERK）, p67phox and Nox-2 in TLR4- and TLR2-induced ROS generation during interleukin-1 beta （IL-1β） transcription, processing, and secretion. An IRAK1/4 inhibitor, U0126, PD98059, an NADPH oxidase inhibitor （diphenyleneiodonium （DPI））, and a free radical scavenger （N-acetyl cysteine （NAC））-attenuated TLR4 （lipopolysaccharide （LPS））- and TLR2 （Pam3csk4）-induced ROS generation and IL-1β production in THP-1 and primary human monocytes. An IRAK1/4 inhibitor and siRNA-attenuated LPS- and Pam3csk4-induced ERK-IRAK1 association and ERK phosphorylation and activity. LPS and Pam3csk4 also induced IRAK1/4-, ERK- and ROS-dependent activation of activator protein-1 （AP-1）, IL-1β transcription, and IL-1β processing because significant inhibition in AP-1 activity, IL-lp transcription, Pro- and mature IL-p expression, and caspase-1 activity was observed with PD98059, U0126, DPI, NAC, an IRAK1/4 inhibitor, tanshinone Ila, and IRAK1 siRNA treatment. IRAK-dependent ERK-p67phox interaction, p67phox translocation, and p67phox-Nox-2 interaction were observed. Nox-2 siRNA significantly reduced secreted IL-lp, IL-1β transcript, pro- and mature IL-1β expression, and caspase-1 activity indicating a role for Nox-2 in LPS- and Pam3csk4-induced IL-1β production, transcription, and processing. In the present study, we demonstrate that the TLR4- and TLR2-induced IRAK-ERK pathway cross-talks with p67phox-Nox-2 for ROS generation, thus regulating IL-1β transcription and orocessin; in monocvtic cells.
ISSN:1672-7681
2042-0226