Lysophosphatidic acid increases soluble ST2 expression in mouse lung and human bronchial epithelial cells

Zhao, Jing; Chen, Qingyuan; Li, Hong; Myerburg, Michael M.; Spannhake, E. W.; Natarajan, Viswanathan; Zhao, Yutong

doi:10.1016/j.cellsig.2011.08.004

Cited by 22 publications

(18 citation statements)

References 51 publications

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“…These results may be reconciled with our findings by considering that ST2 promoter usage appears to be highly cell-type dependent and that fibroblasts may not be the major source of circulating sST2. Human endothelial cells, immune cells, and lung epithelial cells are known to express high levels of sST2 and might be the major source of circulating sST2 (40,44). We found that IL1RL1 intracellular variants associated with higher sST2 concentrations on a population level were also associated with higher sST2 protein levels in KU812 human basophils as well as in A549, U937, and Jurkat T cells.…”

Section: Discussionsupporting

confidence: 48%

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

Ho¹,

Chen²,

Chen³

et al. 2013

J. Clin. Invest.

106

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The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.

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Section: Discussionsupporting

confidence: 48%

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

Ho¹,

Chen²,

Chen³

et al. 2013

J. Clin. Invest.

106

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“…7, D and E). We have shown that LPS treatment reduces lung epithelial integrity (40,41). Here, we showed that LPS increased dextran leak in MLE12 cells (Fig.…”

Section: Erk Regulates Cortactin Ubiquitination and Degradation-mentioning

confidence: 63%

“…We have shown that LPS potently induces cytokine release (39) and epithelial barrier disruption (40,41). LPS treatment also induced cortactin degradation in a time- (Fig.…”

Section: Lps Induces Cortactin Degradation In Lung Epithelial Cells Amentioning

confidence: 99%

Extracellular Signal-regulated Kinase (ERK) Regulates Cortactin Ubiquitination and Degradation in Lung Epithelial Cells

Zhao

Wei

Mialki

et al. 2012

Journal of Biological Chemistry

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Background: Cortactin is essential for barrier integrity. Results: ERK inhibition attenuates cortactin phosphorylation, ubiquitination, and degradation via the ␤-Trcp-mediated ubiquitin-proteasome system. Conclusion: Cortactin stability is coordinately regulated by stress kinases and the ubiquitin-proteasomal network. Significance: Understanding cortactin stability provides new targets to regulate epithelial barrier integrity.

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“…ST2L is a classic type I membrane receptor, containing three extracellular IgG-like domains, a transmembrane domain, and an intracellular Toll/IL-1 receptor (TIR) domain (18). We have demonstrated that lysophosphatidic acid regulates sST2 gene expression in human lung epithelia (19). Recently, we also showed that ST2L is ubiquitinated and degraded in response to IL-33 (5).…”

Section: Introductionmentioning

confidence: 99%

Focal Adhesion Kinase–Mediated Activation of Glycogen Synthase Kinase 3β Regulates IL-33 Receptor Internalization and IL-33 Signaling

Zhao

Wei

Bowser

et al. 2015

The Journal of Immunology

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IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. ST2L, the receptor for IL-33, is expressed on immune effector cells and lung epithelia, and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system, however its upstream internalization has not been studied. Here, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β binding site mutant (ST2LS446A) and phosphorylation site mutant (ST2LS442A) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3β activation and ST2L internalization. Further, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3β might serve as a unique strategy to lessen pulmonary inflammation.

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Lysophosphatidic acid increases soluble ST2 expression in mouse lung and human bronchial epithelial cells

Cited by 22 publications

References 51 publications

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

Extracellular Signal-regulated Kinase (ERK) Regulates Cortactin Ubiquitination and Degradation in Lung Epithelial Cells

Focal Adhesion Kinase–Mediated Activation of Glycogen Synthase Kinase 3β Regulates IL-33 Receptor Internalization and IL-33 Signaling

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