Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway
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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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In vivo studies indicate a requirement for STAT3β during endotoxic assault, a requirement for STAT3α in IL-8 synthesis, and differential roles for STAT3α and STAT3β in anti-inflammatory responses.
“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]
The Abstract and Discussion report that STAT3 participates in Ox-PAPC-induced IL-8 synthesis in human endothelial cells; the Discussion says a dominant-negative STAT3β construct inhibited that response. The paper does not directly establish a specific requirement for STAT3α, and the reported experiment was in cultured cells, not in vivo. The other clauses of the citing sentence have separate citations and are not attributed to this source. (LLM, conf=0.85)
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- 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
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Physiology › 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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