title: Lysophosphatidic acid increases soluble ST2 expression in mouse lung and human bronchial epithelial cells.
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.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Myerburg
authors.forename: Ernst Wm
authors.initials: EW
authors.lastname: Spannhake
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D001980:Bronchi / Q000166:cytology*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D006657:Histones; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008246:Lysophospholipids; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D049368:Receptors, Lysophosphatidic Acid; D018808:Transcription Factor AP-1; D051548:Histone Acetyltransferases; C492429:AGK protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; C032881:lysophosphatidic acid