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Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells
Open accessAbstract
Mice homozygous for the F759 mutation in the gp130 interleukin (IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription (STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex (MHC) II–restricted CD4+ T cells and IL-6 family cytokines. In spite of the necessity for CD4+ T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4+ T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti–IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4+ T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.
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“Further, they act on fibroblasts and endothelial cells to recruit T helper 17 (Th17) cells, leading to an RA-like joint disease (F759 arthritis) and experimental autoimmune encephalomyelitis (EAE) (54, 66, 99).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [99]
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“In fact, a mutated gp130-mediated excessive production of cytokines and chemokines in non-immune cells in F759 mice is necessary for CD4(+) T-cell proliferation, Th17 cell accumulation in the lesion and the arthritis development (66, 99).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [99]
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“Although the development of F759 arthritis is dependent on Th17 cells, the F759 mutation is required in non-immune cells but not immune cells, clearly indicating that the interaction between non-immune cells and immune cells is crucial for arthritis development in F759 mice (66, 99).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [99]
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“Although the development of F759 arthritis is dependent on Th17 cells, the F759 mutation is required in non-immune cells but not immune cells, clearly indicating that the interaction between non-immune cells and immune cells is crucial for arthritis development in F759 mice (66, 99).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [99]
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OsteoimmunologyPreprint
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InfluentialIL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease
Belarif, L., Danger, R., Kermarrec, L., Nerrière‐Daguin, V., Pengam, S., Durand, T., Mary, C., Kerdreux, E., Gauttier, V., Kucik, A., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci121668 · Cited by 141
“It was previously described that OSM and other members of the IL-6 family could induce IL-7 secretion by fibroblasts (81) and hence could increase proliferation of T lymphocytes.”
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“952 Cell Reports 3, 946–959, March 28, 2013 a2013 The Authors The Epiregulin-ErbB1 Pathway Has a Role in Autoimmune Disease Models We have shown that F759 arthritis is mediated nonhemopoietically, particularly in type 1 collagen cells based on bone marrow transplantation and a tissue-specific-deficient system (Murakam…”
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Self-citationTh17 cell induction and immune regulatory effects
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“Whether STAT4 is required for IL-23-dependent effects on developing Th17 cells that are unrelated to IL-17 production remains to be determined, as does a possible role for STAT3 (Sawa et al., 2006).”
BackgroundInfluentialLymphocyte proliferation in immune-mediated diseases
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Interleukin-7 in rheumatoid arthritis
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“In particular, the arthritis which develops in F759 mice requires the presence of CD4þ T cells in addition to gp130 mutation in nonhematopoietic cells, but not CD8þ T cells or B cells (Sawa et al., 2006).”
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“CD4-deficient F759 mice alone attenuated disease development [18].”
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“However, we and others have previously demonstrated that dysregulated homeostatic proliferation of CD4+ T cells can play a role in the development of autoimmune diseases and that homeostatically proliferating CD4+ T cells produce factors that are critical for their development (22, 23).”
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Self-citationIL-17-producing T cells can augment autoantibody-induced arthritis
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“have implicated STAT3 and osteopontin in rheumatoid arthritis (28, 29).”
BackgroundLymphopenia, Lymphopenia-Induced Proliferation, and Autoimmunity
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Conditional gp130 deficient mouse mutants
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“hanced gp130-mediated STAT3 activation and develop lymphocyte-mediated RA-like joint disease [62].”
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“chronic inflammations in tissue-specific MHC class”
InfluentialSelf-citationKDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR
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“For instance, it was recently shown that enhanced IL-6 signaling caused by a hyperresponsive mutant gp130 receptor (Y759F) promotes pathological induction of autoimmune arthritis (40), and this same mutation was previously associated with increased susceptibility to mortality and bacterial growth during a L.”
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“As a result, gp130 F759 mice had expanded effector memory CD4 T cells [65].”
BackgroundPsoriatic inflammation facilitates the onset of arthritis in a mouse model.
Yamamoto, M., Nakajima, K., Takaishi, M., Kitaba, S., Magata, Y., Kataoka, S., & Sano, S. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.426 · Cited by 49
Interleukin-7 Links T Lymphocyte and Intestinal Epithelial Cell Homeostasis
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“tion in the intestine and other organs [8-10].”
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“In line with this latter study, an earlier report by the same group demonstrated that excessive IL-6 expression increases IL-7 expression, which in turn was associated with the development of autoimmune reaction (57).”
ResultAnimal Models of Rheumatoid Arthritis
Castañeda-Lopez, M. E., Veloz, I. G., Ortiz-Rodriguez, J. M., Castañeda-Miranda, R., Solís-Sánchez, L. O., Vega-Carrillo, H. R., Martínez-Blanco, M. D. R., Trejo-Vázquez, F., Ornelas-Vargas, G., Rodriguez-Sanchez, I. P., et al. (2018) · InTech eBooks · doi:10.5772/intechopen.72554 · Cited by 47
Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients
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Matsuda, K., Shiba, N. N., & Hiraoka, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065173 · Cited by 49
“T cells accelerate the expression of IL-6 and IL-8 by synovial fibroblasts [99], and IL-7 expressed by synovial fibroblasts proliferates T cells [33].”
BackgroundHarwardt, T., Lukas, S., Zenger, M., Reitberger, T., Danzer, D., Theresa, Ü., Munday, D. C., Nevels, M. M., & Paulus, C. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005748 · Cited by 43
IL-6 Mediates the Susceptibility of Glycoprotein 130 Hypermorphs to Toxoplasma gondii
Silver, J. S., Stumhofer, J. S., Passos, S., Ernst, M., & Hunter, C. A. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1004144 · Cited by 42
“In contrast, gp130 Y759F mice develop an autoimmune arthritis driven by STAT3-mediated overproduction of IL-7 (14, 15).”
BackgroundJana, M., Mondal, S., Jana, A., & Pahan, K. (2013) · Immunology · doi:10.1111/imm.12214 · Cited by 41
Identification of interleukin‐7 as a candidate disease mediator in spondylarthritis
Rihl, M., Kellner, H. L., Kellner, W., Barthel, C., Yu, D. T. Y., Tak, P. P., Zeidler, H. K., & Baeten, D. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23998 · Cited by 40
“Whereas the best known function of IL-7 is to shape the CD8 cytotoxic T cell repertoire, which may be of particular interest in the context of a class I major histocompatibility complex–associated disease such as SpA, several other roles in human and experimental arthritis have recently been defined (8,9): in the infl…”
BackgroundLupus érythémateux systémique et lymphopénie : aspects cliniques et physiopathologiques
Martin, M., Guffroy, A., Argemi, X., & Martin, T. (2017) · La Revue de Médecine Interne · doi:10.1016/j.revmed.2017.01.005 · Cited by 39
Expression and function of interleukin-7 in secondary and tertiary lymphoid organs
Huang, H.-Y., & Luther, S. A. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.02.008 · Cited by 39
van Roon, J. A. G., Hartgring, S. A. Y., van der Wurff‐Jacobs, K. M. G., Bijlsma, J. W. J., & Lafeber, F. P. J. G. (2010) · Lara D. Veeken · doi:10.1093/rheumatology/keq237 · Cited by 38
Mechanisms of osteoclast activation in inflammatory bone loss in rheumatoid arthritis
Rauner, M., & Bözec, A. (2025) · Nature Reviews Rheumatology · doi:10.1038/s41584-025-01323-9 · Cited by 44
Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis
Ashouri, J. F., Hsu, L., Yu, S., Rychkov, D., Chen, Y., Cheng, D. A., Sirota, M., Hansen, E., Lattanza, L. L., Zikherman, J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904271116 · Cited by 35
“Its overexpression appears to inhibit TCR signaling and T helper cell proliferation (75, 77), whereas decreased SOCS3 activity has been implicated in murine autoimmune arthritis (81-83) and in human RA (48, 78-80).”
BackgroundOta, M., Tanaka, Y., Nakagawa, I., Jiang, J., Arima, Y., Kamimura, D., Onodera, T., Iwasaki, N., & Murakami, M. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41182 · Cited by 35
“naling caused by the lack of a suppressor of cytokine signaling 3–binding site on the IL6 receptor gp130 (21,23).”
BackgroundSelf-citationThe gateway theory: bridging neural and immune interactions in the CNS
Kamimura, D., Yamada, M., Harada, M., Sabharwal, L., Meng, J., Bando, H., Ogura, H., Atsumi, T., Arima, Y., & Murakami, M. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00204 · Cited by 35
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“Consistently, the injection of IL-17 and IL-6 into F759 mice accelerated the development of the joint disease and induced further production of IL-6, suggesting a positive feedback loop (20).”
BackgroundInfluentialSelf-citationGagnon, J., Chen, X. L., Forand‐Boulerice, M., LeBlanc, C., Raman, C., Ramanathan, S., & Ilangumaran, S. (2010) · Immunology and Cell Biology · doi:10.1038/icb.2009.109 · Cited by 35
Hartgring, S. A. Y., Willis, C. R., Bijlsma, J. W. J., Lafeber, F. P. J. G., & van Roon, J. A. G. (2012) · Arthritis Research & Therapy · doi:10.1186/ar3870 · Cited by 33
“Blocking IL-7 prevents gp-130-dependent autoimmune arthritis in mice [17].”
BackgroundAndersson, K., Cavallini, N. F., Hu, D., Brisslert, M., Cialic, R., Valadi, H., Erlandsson, M. C., Silfverswärd, S. T., Pullerits, R., Kuchroo, V. K., et al. (2015) · Molecular Medicine · doi:10.2119/molmed.2015.00057 · Cited by 33
The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis
Kreft, K. L., Verbraak, E., Wierenga‐Wolf, A. F., van Meurs, M., Oostra, B. A., Laman, J. D., & Hintzen, R. Q. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102559 · Cited by 30
Constitutive STAT3 activation in peripheral CD3+cells from patients with primary Sjögren's syndrome
Ramos, H. L., Pacheco, G. V., & Alcocer-Varela, J. C. (2008) · Scandinavian Journal of Rheumatology · doi:10.1080/03009740701606010 · Cited by 30
Arthritogenic T cells in autoimmune arthritis
Komatsu, N., & Takayanagi, H. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.11.008 · Cited by 29
Recent advances in neutralizing the IL-6 pathway in arthritis
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“90 Thus, conditional KO of Stat3 in non-lymphoid cells confirmed that the elevated production of IL-7 and expansion of CD4 + cells was dependent on the activation of Stat3 by IL-6 family cytokines.”
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“Evidence was obtained that the elevation of IL-17 in these mice might be due to a marked increase in IL-7, a recently described promoter of IL-17 (Sawa et al., 2006; 2009; Liu et al., 2010).”
BackgroundHoffmann, M. H., Kirchner, H., Krönke, G., Riemekasten, G., & Bonelli, M. M. (2024) · Annals of the Rheumatic Diseases · doi:10.1136/ard-2023-224092 · Cited by 25
“208 Thus, multiple mutual effects between SFs and T cells have been described, which can be inhibitory as well as stimulatory on T cells in human co-culture systems.”
BackgroundTranscription factors in autoimmune diseases
Stanford, L. P. (2008) · Frontiers in bioscience · doi:10.2741/3001 · Cited by 24
“Otherwise, some work has implicated STAT3 as a potentially protective member, since overexpression of the STAT3 inhibitor SOCS-3 protects against collageninduced arthritis (57); but the Jak2-STAT3 pathway has been implicated in the pathogenesis of arthritis in IL-1RAdeficient and gp130 F759 mice (58, 59).”
BackgroundYahagi, A., Saika, T., Hirano, H., Takai-Imamura, M., Tsuji, F., Aono, H., Iseki, M., Morita, Y., Igarashi, H., Saeki, Y., et al. (2019) · RMD Open · doi:10.1136/rmdopen-2018-000853 · Cited by 22
“However, the final incidence of disease was unaffected.(18) In the preclinical phase of gp130F759 in this study, deletion of IL-6 resulted in the reduction of splenomegaly, CRP, RF, PAD4 production, anti-CCP-IgM and synovial cell numbers, indicating that these parameters are IL-6-dependent and that IL-6 is critically…”
BackgroundSelf-citationB cell–derived IL-1β and IL-6 drive T cell reconstitution following lymphoablation
Hasgur, S., Fan, R., Zwick, D. B., Fairchild, R. L., & Valujskikh, A. (2020) · American Journal of Transplantation · doi:10.1111/ajt.15960 · Cited by 22
ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons
Hasebe, R., Murakami, K., Harada, M., Halaka, N., Nakagawa, H., Kawano, F., Ohira, Y., Kawamoto, T., Yull, F. E., Blackwell, T. S., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20212019 · Cited by 21
“Importantly, F759 arthritis was developed even in RAG-deficient F759 mice (Sawa et al., 2006), although F759 arthritis is dependent on Th17 cells expressing IL17A and IL-6 in a non-RAG-deficient background followed by activation of the IL-6 amplifier in joints by these cytokines (Murakami et al.”
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Perspectives of the relationship between IL-7 and autoimmune diseases
Wang, X., Li, B., Hu, L., Wen, P., Zhang, M., Pan, H., & Ye, D. (2013) · Clinical Rheumatology · doi:10.1007/s10067-013-2360-x · Cited by 22
The Discovery of Novel Experimental Therapies for Inflammatory Arthritis
Malemud, C. J. (2009) · Mediators of Inflammation · doi:10.1155/2009/698769 · Cited by 21
“[56] who showed that mice homozygous for the F759 mutation in the gp130/IL-6R subunit showed elevated Stat3 activation and a rheumatoid-like arthritic joint disease.”
BackgroundAskmyr, M., White, K. E., Jovic, T., King, H. A. D., Quach, J., Maluenda, A. C., Baker, E. K., Smeets, M. F. M. A., Walkley, C. R., & Purton, L. E. (2015) · Scientific Reports · doi:10.1038/srep15529 · Cited by 20
Jin, J., & Yu, Q. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0712360 · Cited by 20
“Moreover, IFN- and IL-6 promote IL-7 production in intestinal epithelial cells [45, 46] and fibroblasts [47], respectively.”
BackgroundIntegration of B cells and CD8+ T in the protective regulation of systemic epithelial inflammation
Wei, B., McPherson, M., Turovskaya, O., Velázquez, P., Fujiwara, D., Brewer, S., & Braun, J. G. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.01.001 · Cited by 19
“Self-reactive CD4+ T cell activation and systemic disease in lymphopenia is augmented by genetically targeting of proliferative or effector molecules [53–57].”
BackgroundSato‐Hayashizaki, A., Ohtsuji, M., Lin, Q., Hou, R., Ohtsuji, N., Nishikawa, K., Tsurui, H., Sudo, K., Ono, M., Izui, S., et al. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30485 · Cited by 18
Metadata
- Authors
- Sawa, S.-I., Kamimura, D., Jin, G.-H., Morikawa, H., Kamon, H., Nishihara, M., Ishihara, K., Murakami, M., & Hirano, T.
- Affiliations
- 1Laboratory of Developmental Immunology, Graduate School of Frontier Bioscience and Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
- RIKEN (JP)
- The University of Osaka (JP)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-05-22
- Volume
- 203
- Issue
- 6
- Pages
- 1459-1470
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118324
- OpenAlex
- W2133947803
- Cited by
- 176
- References
- 49
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 6 · 2015: 16 · 2014: 8 · 2013: 9 · 2012: 19
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- autoimmune arthritis, gp130, IL-6 receptor, STAT3, IL-7, IL-6 family cytokines, MHC class II-restricted T cells, non-hematopoietic cells
- MeSH terms
- Animals, Arthritis, Autoimmune Diseases, Disease Models, Animal, Flow Cytometry, Homeostasis, Homozygote, Humans, Lymphocyte Activation, Mice, Inbred C57BL, Mutation, Thymectomy, CD4-Positive T-Lymphocytes, Interleukin-7, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice
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