Abstract
Lysophosphatidic acid (LPA), a naturally occurring bioactive lysophospholipid increases the expression of both pro-inflammatory and anti-inflammatory mediators in airway epithelial cells. Soluble ST2 (sST2), an anti-inflammatory mediator, has been known to function as a decoy receptor of interleukin (IL)-33 and attenuates endotoxin-induced inflammatory responses. Here, we show that LPA increased sST2 mRNA expression and protein release in a dose and time dependent manner in human bronchial epithelial cells (HBEpCs). LPA receptors antagonist and Gαi inhibitor, pertussis toxin, attenuated LPA-induced sST2 release. Inhibition of NF-κB or JNK pathway reduced LPA-induced sST2 release. LPA treatment decreased histone deacetylase 3 (HDAC3) expression and enhanced acetylation of histone H3 at lysine 9 that binds to the sST2 promoter region. Furthermore, limitation of intracellular LPA generation by the down-regulation of acetyl glycerol kinase attenuated exogenous LPA-induced histone H3 acetylation on sST2 promoter region, as well as sST2 gene expression. Treatment of HBEpCs with recombinant sST2 protein or sST2-rich cell culture media attenuated endotoxin-induced phosphorylation of PKC and airway epithelial barrier disruption. These results unravel a novel sST2 mediated signaling pathway that has physiological relevance to airway inflammation and remodeling.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylation
-
Animals
-
Base Sequence
-
Bronchi / cytology*
-
Cell Line
-
Epithelial Cells / drug effects
-
Epithelial Cells / metabolism*
-
Gene Knockdown Techniques
-
Histone Acetyltransferases / metabolism
-
Histones / metabolism
-
Humans
-
Interleukin-1 Receptor-Like 1 Protein
-
Lung / cytology
-
Lung / drug effects
-
Lung / metabolism*
-
Lysophospholipids / metabolism
-
Lysophospholipids / pharmacology
-
Lysophospholipids / physiology*
-
Mice
-
Molecular Sequence Data
-
NF-kappa B / metabolism
-
Phosphorylation
-
Phosphotransferases (Alcohol Group Acceptor) / genetics
-
Phosphotransferases (Alcohol Group Acceptor) / metabolism
-
Promoter Regions, Genetic
-
Protein Kinase C / metabolism
-
RNA Interference
-
Receptors, Cell Surface / genetics
-
Receptors, Cell Surface / metabolism*
-
Receptors, Lysophosphatidic Acid / agonists
-
Receptors, Lysophosphatidic Acid / metabolism
-
Respiratory Mucosa / cytology
-
Respiratory Mucosa / drug effects
-
Respiratory Mucosa / metabolism*
-
Sequence Analysis, DNA
-
Signal Transduction
-
Transcription Factor AP-1 / metabolism
-
Transcription, Genetic
Substances
-
Histones
-
IL1RL1 protein, human
-
Interleukin-1 Receptor-Like 1 Protein
-
Lysophospholipids
-
NF-kappa B
-
Receptors, Cell Surface
-
Receptors, Lysophosphatidic Acid
-
Transcription Factor AP-1
-
Histone Acetyltransferases
-
AGK protein, human
-
Phosphotransferases (Alcohol Group Acceptor)
-
Protein Kinase C
-
lysophosphatidic acid