Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
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Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractant, following postpartum Gram-negative bacterial infection. The present study examined the impact of the IL6R/STAT3 signaling pathway on IL-8 production by primary endometrial cells in response to short- or long-term exposure to lipopolysaccharide (LPS) from Gram-negative bacteria. Tyrosine phosphorylation of STAT3 is required for DNA binding and expression of specific targets genes. Immunoblotting indicated constitutive tyrosine phosphorylation of STAT3 in endometrial cells was impeded by acute exposure to LPS. After 24 h exposure to LPS, STAT3 returned to a tyrosine phosphorylated state, indicating cross-talk between the Toll-like receptor 4 (TLR4) and the IL6R/STAT3 signaling pathways. This was confirmed by short interfering RNA targeting the IL6R, which abrogated the accumulation of IL-6 and IL-8, induced by LPS. Furthermore, there was a differential endometrial cell response, as the accumulation of IL-6 and IL-8 was dependent on STAT3, suppressor of cytokine signaling 3, and Src kinase signaling in stromal cells, but not epithelial cells. In conclusion, positive feedback through the IL6R amplifies LPS-induced IL-6 and IL-8 production in the endometrium. These findings provide a mechanistic insight into how elevated IL-6 concentrations in the postpartum endometrium during bacterial infection leads to marked and sustained neutrophil infiltration.
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IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.
“IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.31,32,33,34”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [32]
The Introduction states that IL-6 activates STAT3 through the IL-6 receptor, and the Discussion says IL6R activation changes target-gene expression via STAT3. Neither passage supports the claimed metabolic actions; the paper discusses inflammatory responses in endometrial cells. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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- Authors
- Cronin, J. G., Kanamarlapudi, V., Thornton, C. A., & Sheldon, I. M.
- Affiliations
- Swansea University (GB)
- Corresponding author
- Cronin, J.G.
- Sheldon, I.M.
- Venue
- Mucosal Immunology
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 9
- Issue
- 5
- Pages
- 1125-1136
- ISSN
- 1933-0219 (ISSN-L)
- PMC
- PMC4990777
- OpenAlex
- W2336394695
- Cited by
- 73
- References
- 50
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 11 · 2020: 8 · 2019: 11 · 2018: 7 · 2017: 5 · 2016: 2
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Mucosal Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/I017240/1, BB/F005121/1, BB/C515455/2, F005121/1, BB/C515455/1)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Agricultural and Biological Sciences › Agronomy and Crop Science › Reproductive Physiology in Livestock
- Keywords
- STAT3, TLR4, interleukin-6, interleukin-8, IL-6 receptor, positive feedback loop, endometrium, lipopolysaccharide, bovine endometritis, neutrophil recruitment, SOCS3, Src kinase signaling, gram-negative bacterial infection, postpartum infection, endometrial stromal cells, endometrial epithelial cells
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cattle, Cell Separation, Endometrium, Epithelial Cells, Female, Gene Expression Regulation, Lipopolysaccharides, Signal Transduction, Interleukin-6, Interleukin-8, Stromal Cells, Coculture Techniques, Receptors, Interleukin-6, Feedback, Physiological, RNA, Small Interfering, STAT3 Transcription Factor, Toll-Like Receptor 4, Primary Cell Culture
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