General nature of the STAT3-activated anti-inflammatory response.
Abstract
Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.
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Blocking SOCS3's ability to inhibit IL-6 signaling leads to an anti-inflammatory response indistinguishable from that induced by IL-10 in macrophages.
“Two independent experiments demonstrated that blocking SOCS3's ability to inhibit IL-6 signaling leads to an anti-inflammatory response indistinguishable from that induced by IL-10 in macrophages [12], [13].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [13]
IL-10R has two motifs for STAT3 activation while the gp130 subunit of IL-6R has four, leading to IL-6R inducing a higher amplitude STAT3 signal.
“Another key difference between the IL-10R and the IL-6R, besides their differing interactions with SOCS3, is that the IL-10R has two motifs for STAT3 activation while the gp130 subunit of the IL-6R has four, leading to the IL-6R inducing a higher amplitude STAT3 signal [13], [27], [28].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [13]
The altered EPOR induced an anti-inflammatory response indistinguishable from IL-10.
“This altered form of the EPOR induced an anti-inflammatory response indistinguishable from IL-10, which also supports the hypothesis that signal duration is a determinant of whether or not a response is inflammatory or anti-inflammatory [13].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [13]
The altered EPOR result supports the hypothesis that signal duration is a determinant of whether a response is inflammatory or anti-inflammatory.
“This altered form of the EPOR induced an anti-inflammatory response indistinguishable from IL-10, which also supports the hypothesis that signal duration is a determinant of whether or not a response is inflammatory or anti-inflammatory [13].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [13]
El Kasmi et al. developed a system for analyzing signal duration in inflammatory response by transfecting macrophages with an altered EPOR capable of inducing pSTAT3 and not susceptible to SOCS3 inhibition.
“As further evidence of signal duration being a defining feature in determining the inflammatory response, El Kasmi et. al. also developed a system for analyzing this problem [13]. They transfected macrophages with an altered form of the EPO receptor (EPOR), which was capable of inducing pSTAT3 and was not susceptible to SOCS3 inhibition.”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [13]
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References 65 · Cited by 225
- Authors
- El Kasmi, K. C., Holst, J., Coffre, M., Mielke, L., de Pauw, A., Lhocine, N., Smith, A. M., Rutschman, R., Kaushal, D., Shen, Y., Suda, T., Donnelly, R. P., Myers, M. G., Alexander, W., Vignali, D. A. A., Watowich, S. S., Ernst, M., Hilton, D. J., & Murray, P. J.
- Affiliations
- Department of Infectious Diseases, St. Jude Children’s Research Hospital , Memphis, TN 38105
- St. Jude Children's Research Hospital (US)
- The Royal Melbourne Hospital (AU)
- Rockefeller University (US)
- Kanazawa University (JP)
- United States Food and Drug Administration (US)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-12-01
- Volume
- 177
- Issue
- 11
- Pages
- 7880-7888
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2122093149
- Cited by
- 225
- References
- 65
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 12 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 13 · 2016: 15 · 2015: 8 · 2014: 16 · 2013: 15 · 2012: 16
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P 30CA 21765, P30CA021765)
- National Institute of Allergy and Infectious Diseases (AI 062961)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- STAT3, anti-inflammatory response, IL-10 receptor, cytokine receptor signaling, SOCS3, IL-22 receptor, IL-6 receptor, leptin receptor, erythropoietin receptor, innate immune response, cytokine signaling pathways
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Enzyme-Linked Immunosorbent Assay, Inflammation, Immunoblotting, Signal Transduction, Interleukin-6, Gene Expression, Interleukin-10, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice, Receptors, Interleukin-10
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