IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages
Abstract
Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.
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Mice conditionally deficient for Socs3 revealed SOCS3 to be a potent physiological suppressor of IL-6 but not IFNγ signaling.
“the generation of mice conditionally deficient for Socs3 revealed SOCS3 to be a potent physiological suppressor of IL-6 but not IFN␥ signaling (24 -26).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [26]
Each of these stimuli activates the glycoprotein-130/STAT3 or G-CSF-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo.
“Interestingly, each of these stimuli activates the glycoprotein-130/STAT3 or the granulocytecolony stimulating factor-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo (24 -26, 29, 40, 41).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [26]
SOCS3 expression is necessary for the pro-inflammatory effects of IL-6.
“SOCS3 expression is necessary for the pro-inflam- matory effects of IL-6 (26).”
From Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation (2013) · cites this paper as [26]
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 [12]
Yasukawa et al. exposed SOCS3−/− macrophages to IL-6 and LPS and measured TNF and IL-12(p40) in the supernatant, showing that IL-6 acted anti-inflammatory.
“A revealing experiment performed by Yasukawa et. al. in which they exposed SOCS3−/−macrophages to IL-6 and LPS and measured the concentration of two pro-inflammatory cytokines (TNF and IL-12(p40)) in the supernatant showed just the opposite [12].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [12]
In Yasukawa et al., as IL-6 dosage increased, pro-inflammatory cytokine concentration dropped, meaning IL-6 acted as an anti-inflammatory cytokine on SOCS3−/− macrophages.
“As the dosage of IL-6 was increased, the pro-inflammatory cytokine concentration dropped meaning that IL-6 was acting as an anti-inflammatory cytokine on the SOCS3−/− macrophages.”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [12]
The model predicts no distinction between IL-10 acting on SOCS3−/− vs WT macrophages, as observed.
“Since there is no distinction between IL-10 acting on SOCS3−/− or WT macrophages, the model predicts that no distinction will be seen experimentally, as was observed [12].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [12]
Both IL-6 and IL-10 activate STAT3 but confer opposite effects because of differential effects of SOCS3.
“Although both IL-6 and IL-10 activate STAT3, they confer opposite effects because of differential effects of SOCS3, induced by each”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Yasukawa et al., 2003
Cites
Interleukin-10 and the Interleukin-10 Receptor
Moore, K. W., de Waal Malefyt, R., Coffman, R. L., & O'Garra, A. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.683 · Cited by 6,737 · see citing works
SOCS1/JAB Is a Negative Regulator of LPS-Induced Macrophage Activation
Kinjyo, I., Hanada, T., Inagaki-Ohara, K., Mori, H., Aki, D., Ohishi, M., Yoshida, H., Kubo, M., & Yoshimura, A. (2002) · Immunity · doi:10.1016/s1074-7613(02)00446-6 · Cited by 630 · see citing works
Self-citationAtsumi, T., Ishihara, K., Kamimura, D., Ikushima, H., Ohtani, T., Hirota, S., Kobayashi, H., Park, S.-J., Saeki, Y., Kitamura, Y., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020619 · Cited by 225 · see citing works
Self-citationLPS and TNFα induce SOCS3 mRNA and inhibit IL‐6‐induced activation of STAT3 in macrophages
Bode, J. G., Nimmesgern, A., Schmitz, J., Schaper, F., Schmitt, M., Frisch, W., Häussinger, D., Heinrich, P. C., & Graeve, L. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01662-2 · Cited by 196 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
de Jonge, W. J., van der Zanden, E. P., The, F. O., Bijlsma, M. F., van Westerloo, D. J., Bennink, R. J., Berthoud, H.-R., Uematsu, S., Akira, S., van den Wijngaard, R. M., et al. (2005) · Nature Immunology · doi:10.1038/ni1229 · Cited by 1,074 · see citing works
Self-citationThe microbiota regulates type 2 immunity through RORγt <sup>+</sup> T cells
Ohnmacht, C., Park, J.-H., Cording, S., Wing, J. B., Atarashi, K., Obata, Y., Gaboriau-Routhiau, V., Marques, R., Dulauroy, S., Fedoseeva, M., et al. (2015) · Science · doi:10.1126/science.aac4263 · Cited by 863 · see citing works
Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., Torisu, T., Chien, K. R., Yasukawa, H., & Yoshimura, A. (2004) · Nature Medicine · doi:10.1038/nm1071 · Cited by 651 · see citing works
Self-citationSOCS3, a Major Regulator of Infection and Inflammation
Carow, B., & Rottenberg, M. E. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00058 · Cited by 555 · see citing works
Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
Ruess, D. A., Heynen, G. J., Ciecielski, K. J., Ai, J., Berninger, A., Kabacaoglu, D., Görgülü, K., Dantes, Z., Wörmann, S. M., Diakopoulos, K. N., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0024-8 · Cited by 370 · see citing works
Interleukin-6, a mental cytokine
Spooren, A., Kolmus, K., Laureys, G., Clinckers, R., De Keyser, J., Haegeman, G., & Gerlo, S. (2011) · Brain Research Reviews · doi:10.1016/j.brainresrev.2011.01.002 · Cited by 352 · see citing works
Signal transduction of inflammatory cytokines and tumor development
Yoshimura, A. (2006) · Cancer Science · doi:10.1111/j.1349-7006.2006.00197.x · Cited by 314 · see citing works
Self-citationBharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Although both IL-6 and IL-10 activate STAT3, they confer opposite effects because of differential effects of SOCS3, induced by each (Yasukawa et al., 2003).”
BackgroundKershaw, N. J., Murphy, J. M., Liau, N. P. D., Varghese, L. N., Laktyushin, A., Whitlock, E. L., Lucet, I. S., Nicola, N. A., & Babon, J. J. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2519 · Cited by 301 · see citing works
Tet2 restrains inflammatory gene expression in macrophages
Cull, A. H., Snetsinger, B., Buckstein, R., Wells, R. A., & Rauh, M. J. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.08.001 · Cited by 295 · see citing works
IL-6 <i>Trans</i>-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Greenhill, C. J., Rose-John, S., Lissilaa, R., Ferlin, W., Ernst, M., Hertzog, P. J., Mansell, A., & Jenkins, B. J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002971 · Cited by 264 · see citing works
Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences
Donzis, E. J., & Tronson, N. C. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.08.008 · Cited by 254 · see citing works
O'Donovan, A., Rush, G., Hoatam, G., Hughes, B. M., McCrohan, A., Kelleher, C., O'Farrelly, C., & Malone, K. M. (2013) · Depression and Anxiety · doi:10.1002/da.22087 · Cited by 210 · see citing works
El Kasmi, K. C., Smith, A. M., Williams, L., Neale, G., Panopolous, A., Watowich, S. S., Häcker, H., Foxwell, B. M. J., & Murray, P. J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7215 · Cited by 182 · see citing works
Polarization of Rheumatoid Macrophages by TNF Targeting Through an IL-10/STAT3 Mechanism
Degboé, Y., Rauwel, B., Baron, M., Boyer, J.-F., Ruyssen-Witrand, A., Constantin, A., & Davignon, J.-L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00003 · Cited by 174 · see citing works
Detection of differentially abundant cell subpopulations in scRNA-seq data
Zhao, J., Jaffe, A., Li, H., Lindenbaum, O., Sefik, E., Jackson, R., Cheng, X., Flavell, R. A., & Kluger, Y. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2100293118 · Cited by 154 · see citing works
Braun, D. A., Fribourg, M., & Sealfon, S. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.386573 · Cited by 168 · see citing works
Babon, J. J., McManus, E. J., Yao, S., DeSouza, D. P., Mielke, L. A., Sprigg, N. S., Willson, T. A., Hilton, D. J., Nicola, N. A., Baca, M., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.024 · Cited by 163 · see citing works
Hirotani, T., Yamamoto, M., Kumagai, Y., Uematsu, S., Kawase, I., Takeuchi, O., & Akira, S. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.12.184 · Cited by 135 · see citing works
Self-citationWormald, S., Zhang, J.-G., Krebs, D. L., Mielke, L. A., Silver, J., Alexander, W. S., Speed, T. P., Nicola, N. A., & Hilton, D. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509595200 · Cited by 123 · see citing works
Kimura, A., Kinjyo, I., Matsumura, Y., Mori, H., Mashima, R., Harada, M., Chien, K. R., Yasukawa, H., & Yoshimura, A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c300496200 · Cited by 119 · see citing works
Self-citationSuppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy
Chikuma, S., Kanamori, M., Mise‐Omata, S., & Yoshimura, A. (2017) · Cancer Science · doi:10.1111/cas.13194 · Cited by 112 · see citing works
Self-citationCronin, J. G., Kanamarlapudi, V., Thornton, C. A., & Sheldon, I. M. (2016) · Mucosal Immunology · doi:10.1038/mi.2015.131 · Cited by 73 · see citing works
Lessard, A.-J., LeBel, M., Egarnes, B., Préfontaine, P., Thériault, P., Droit, A., Brunet, A., Rivest, S., & Gosselin, J. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.009 · Cited by 70 · see citing works
Cianciulli, A., Calvello, R., Porro, C., Trotta, T., & Panaro, M. A. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.07.005 · Cited by 59 · see citing works
Miki, S., Suzuki, J.-I., Takashima, M., Ishida, M., Kokubo, H., & Yoshizumi, M. (2021) · Scientific Reports · doi:10.1038/s41598-021-01866-3 · Cited by 58 · see citing works
Chamberlain, T. C., Cheung, S. T., Yoon, J. S. J., Ming-Lum, A., Gardill, B. R., Shakibakho, S., Dzananovic, E., Ban, F., Samiea, A., Jawanda, K., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101433 · Cited by 32 · see citing works
Hutchins, A. P., Diez, D., & Miranda-Saavedra, D. (2013) · JAK-STAT · doi:10.4161/jkst.25097 · Cited by 31 · see citing works
Sobotta, S., Raue, A., Huang, X., Vanlier, J., Jünger, A., Bohl, S., Albrecht, U., Hahnel, M. J., Wolf, S., Mueller, N. S., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00775 · Cited by 28 · see citing works
“Distinct from IL-6, IL-10 apparently does not induce the expression of suppressor of cytokine signaling 3 (SOCS3), (Ichikawa et al., 2002) and in mice lacking a functional Socs3 gene in macrophages or neutrophils no obvious alteration in IL-10 signal transduction is observed (Yasukawa et al., 2003).”
BackgroundA Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs
Fowler, K. D., Kuchroo, V. K., & Chakraborty, A. K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033018 · Cited by 6 · see citing works
“in which they exposed SOCS32/2macrophages to IL-6 and LPS and measured the concentration of two pro-inflammatory cytokines (TNF and IL-12(p40)) in the supernatant showed just the opposite [12].”
- Authors
- Yasukawa, H., Ohishi, M., Mori, H., Murakami, M., Chinen, T., Aki, D., Hanada, T., Takeda, K., Akira, S., Hoshijima, M., Hirano, T., Chien, K. R., & Yoshimura, A.
- Affiliations
- University of California San Diego (US)
- Kyushu University (JP)
- The University of Osaka (JP)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Yoshimura, Akihiko
- ORCID
- Venue
- Nature Immunology
- Published
- 2003-05-18
- Volume
- 4
- Issue
- 6
- Pages
- 551-556
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2016313989
- Cited by
- 771
- References
- 4
- Citations by year
- 2026: 7 · 2025: 21 · 2024: 20 · 2023: 27 · 2022: 14 · 2021: 29 · 2020: 33 · 2019: 36 · 2018: 31 · 2017: 28 · 2016: 33 · 2015: 33 · 2014: 37 · 2013: 32 · 2012: 48
- FWCI
- 22.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Research Foundation for Clinical Pharmacology
- Uehara Memorial Foundation
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- interleukin-6, IL-10, SOCS3, STAT3, macrophages, gp130, lipopolysaccharide signaling, TNF-α, IL-12, cytokine signaling regulation, anti-inflammatory response
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Interleukin-6 Inhibitors, Animals, DNA-Binding Proteins, Female, Lipopolysaccharides, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Proteins, Repressor Proteins, Transcription Factors, Tumor Necrosis Factor-alpha, Immunoblotting, Signal Transduction, Trans-Activators, Interleukin-6, Interleukin-10, Macrophages, Peritoneal, Mice, Knockout, src Homology Domains, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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