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Oxidized Phospholipids Increase Interleukin 8 (IL-8) Synthesis by Activation of the c-src/Signal Transducers and Activators of Transcription (STAT)3 Pathway
Open accessAbstract
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and its component phospholipids 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine (PEIPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine induce endothelial cells to synthesize chemotactic factors, such as interleukin 8 (IL-8). We have shown recently that Ox-PAPC-mediated induction of IL-8 transcription is independent of NF-kappaB activation, a major transcription factor utilized by cytokines and lipopolysaccharide for the induction of IL-8 transcription. In this study, we provide evidence for the role of c-src in Ox-PAPC and, specifically, PEIPC-mediated IL-8 induction. Ox-PAPC and its component phospholipids induced a rapid and transient phosphorylation of c-src Tyr418, a hallmark of c-src activation, in human aortic endothelial cells (HAEC). Ox-PAPC-mediated IL-8 protein synthesis in HAEC was inhibited by Src family kinase inhibitors, PP1 and PP2, but not by an inactive analog, PP3. Transient expression of plasmids containing C-terminal Src kinase or kinase-deficient dominant-negative c-src resulted in a 72 and 50% reduction in Ox-PAPC-induced IL-8 promoter activation in human microvascular endothelial cells, respectively. In contrast, overexpression of v-src kinase resulted in a 4-fold increase in IL-8 promoter activation, without inducing NF-kappaB promoter activation. Furthermore, treatment of HAEC with Ox-PAPC and its component PEIPC induced the activation of STAT3 by phosphorylating Tyr705, a feature of STAT3 activation. STAT3 is a known downstream effector of c-src. Ox-PAPC-induced activation of STAT3 resulted in the translocation of STAT3 from the cytoplasm of HAEC into their nuclear compartment. Transient expression of a dominant-negative STAT3beta construct in HMEC strongly inhibited IL-8 induction by Ox-PAPC. Taken together, these data demonstrate the role of the c-src kinase/STAT3 pathway in Ox-PAPC-mediated IL-8 expression in endothelial cells.
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“spliceform-specific functions have been indicated by various in vivo studies showing a requirement for STAT3β during endotoxic assault [16], but a requirement for STAT3α in IL-8 synthesis [17], as well as differential roles for STAT3α and STAT3β in anti-inflammatory responses [15].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [17]
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Metadata
- Authors
- Yeh, M., Gharavi, N. M., Choi, J., Hsieh, X., Reed, E., Mouillesseaux, K. P., Cole, A. L., Reddy, S. T., & Berliner, J. A.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Berliner, Judith A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 279
- Issue
- 29
- Pages
- 30175-30181
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2013661403
- Cited by
- 116
- References
- 46
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 6 · 2014: 8 · 2013: 4 · 2012: 10
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- oxidized phospholipids, interleukin-8, Src kinase, STAT3, endothelial cells, Src family kinases, NF-κB-independent signaling, STAT3 nuclear translocation, v-Src, inflammation, vasoactive mediators
- MeSH terms
- CSK Tyrosine-Protein Kinase, Cyclic AMP, Cell Nucleus, Cells, Cultured, Cytoplasm, DNA-Binding Proteins, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Genes, Dominant, Humans, Inflammation, Kinetics, Models, Biological, Oxygen, Phosphatidylcholines, Phospholipids, Phosphorylation, Plasmids, Protein-Tyrosine Kinases, Time Factors, Transfection, Tyrosine, Blotting, Western, Signal Transduction, Trans-Activators, Interleukin-8, NF-kappa B, Protein Structure, Tertiary, src-Family Kinases, STAT3 Transcription Factor
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