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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IL-6 and sIL-6Rα act on fibroblasts and endothelial cells to recruit Th17 cells, leading to an RA-like joint disease (F759 arthritis) and experimental autoimmune encephalomyelitis (EAE).
“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]
The Results (page not provided) show that IL-6 plus soluble IL-6 receptor induces IL-7 expression in fibroblasts, and that IL-6 contributes to RA-like arthritis in F759 mice. The paper does not establish that fibroblasts or endothelial cells recruit Th17 cells, or link this mechanism to EAE. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMutated 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 arthritis development.
“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]
The Results (page not provided) show that the gp130 mutation in nonhematopoietic cells is necessary for arthritis in F759 mice, and report enhanced IL-7 expression in those cells; the paper also links CD4+ T-cell homeostatic proliferation to disease. Our copy does not establish that excessive production of cytokines and chemokines in non-immune cells is necessary for all these outcomes, and it does not report Th17-cell accumulation in lesions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredF759 arthritis development is dependent on Th17 cells.
“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]
The Results section reports that MHCII-restricted CD4+ T cells are necessary for F759 arthritis. It does not establish that the disease depends specifically on the Th17 subset; searches for “Th17” and “IL-17-producing T helper cells” found no such finding in our copy. Page numbers were not available. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe F759 mutation is required in non-immune cells but not immune cells.
“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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BackgroundInterleukin 6 in autoimmune and inflammatory diseases: a personal memoir
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Self-citationTimmer, T. C. G., Baltus, B., Vondenhoff, M. F. R., Huizinga, T. W. J., Tak, P. P., Verweij, C. L., Mebius, R. E., & Kraan, T. C. T. M. V. D. P. (2007) · Arthritis & Rheumatism · doi:10.1002/art.22748 · Cited by 165 · see citing works
Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis
Gao, W., McCormick, J., Connolly, M., Balogh, E., Veale, D. J., & Fearon, U. (2014) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2013-204105 · Cited by 150 · see citing works
Hara, T., Shitara, S., Imai, K., Miyachi, H., Kitano, S., Yao, H., Tani‐ichi, S., & Ikuta, K. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200586 · Cited by 143 · see citing works
OsteoimmunologyPreprint
Okamoto, K., & Takayanagi, H. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031245 · Cited by 142 · see citing works
“TNF-α and IL-6 are responsible not only for local inflammation but also bone destruction through the up-regulation of RANKL.”
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 138 · see citing works
“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.”
BackgroundWiner, H. Y., Rodrigues, G. O. L., Hixon, J. A., Aiello, F. B., Hsu, T. C., Wachter, B. T., Li, W., & Durum, S. K. (2022) · Cytokine · doi:10.1016/j.cyto.2022.156049 · Cited by 134 · see citing works
The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells
Liu, Z.-M., Wang, K.-P., Ma, J., & Zheng, S. G. (2015) · Cellular and Molecular Immunology · doi:10.1038/cmi.2014.133 · Cited by 120 · see citing works
SOCS3 and its role in associated diseases
Yin, Y., Liu, W., & Dai, Y. (2015) · Human Immunology · doi:10.1016/j.humimm.2015.09.037 · Cited by 113 · see citing works
Disease-association analysis of an inflammation-related feedback loop
Murakami, M., Harada, M., Kamimura, D., Ogura, H., Okuyama, Y., Kumai, N., Okuyama, A., Singh, R., Jiang, J.-J., Atsumi, T., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.028 · Cited by 110 · see citing works
“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…”
BackgroundMethodInfluentialSelf-citationPark, J., Kwok, S., Lim, M., Kim, E., Ryu, J., Kim, S., Oh, H.-J., Ju, J. H., Park, S., Kim, H., et al. (2013) · Arthritis & Rheumatology · doi:10.1002/art.38305 · Cited by 109 · see citing works
Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis
Jones, G. W., Bombardieri, M., Greenhill, C., McLeod, L., Nerviani, A., Rocher-Ros, V., Figueras, A. C., Williams, A. S., Pitzalis, C., Jenkins, B. J., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20132307 · Cited by 105 · see citing works
“Thus, localized STAT3 activity is an unreliable indicator of ELS and is consistent with the broader roles of STAT3 in governing chronic inflammation (Atsumi et al., 2002; Sawa et al., 2006; Nowell et al., 2009).”
BackgroundResultMurakami, M., Okuyama, Y., Ogura, H., Asano, S., Arima, Y., Tsuruoka, M., Harada, M., Kanamoto, M., Sawa, Y., Iwakura, Y., et al. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20100900 · Cited by 100 · see citing works
“As these mice age, they spontaneously develop an RA-like MHC II–associated tissuespecific disease, indicating that constitutive activation of IL-6 signaling is involved in the development of some autoimmune diseases (Atsumi et al., 2002; Sawa et al., 2006).”
InfluentialSelf-citationKomatsu, N., & Takayanagi, H. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00077 · Cited by 98 · see citing works
“In addition, non-hematopoietic cells, presumably synovial fibroblasts, produce elevated levels of IL-7 and IL-6, which enhances the homeostatic proliferation of CD4+T-cells and the production of IL-17 in Th17 cells, respectively (Sawa et al., 2006; Ogura et al., 2008).”
BackgroundCommensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo
Shalapour, S., Deiser, K., Sercan-Alp, Ö., Tuckermann, J. P., Minnich, K., Willimsky, G., Blankenstein, T. J. F., Hämmerling, G. J., Arnold, B., & Schüler, T. (2010) · European Journal of Immunology · doi:10.1002/eji.201040441 · Cited by 93 · see citing works
NEDD4 Is Involved in Inflammation Development during Keloid Formation
Fujita, M., Yamamoto, Y., Jiang, J., Atsumi, T., Tanaka, Y., Ohki, T., Murao, N., Funayama, E., Hayashi, T., Osawa, M., et al. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.07.044 · Cited by 93 · see citing works
Self-citationTh17 cell induction and immune regulatory effects
Bi, Y., Liu, G., & Yang, R. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.20973 · Cited by 91 · see citing works
“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
Datta, S., & Sarvetnick, N. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.06.002 · Cited by 91 · see citing works
Hartgring, S. A. Y., Willis, C. R., Alcorn, D., Nelson, L. J., Bijlsma, J. W. J., Lafeber, F. P. J. G., & van Roon, J. A. G. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27578 · Cited by 90 · see citing works
Interleukin-7 in rheumatoid arthritis
Churchman, S. M., & Ponchel, F. (2008) · Lara D. Veeken · doi:10.1093/rheumatology/ken053 · Cited by 89 · see citing works
Komatsu, N., & Takayanagi, H. (2012) · Advances in immunology · doi:10.1016/b978-0-12-394299-9.00002-3 · Cited by 88 · see citing works
“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).”
Hartgring, S. A. Y., van Roon, J. A. G., Wijk, M. W.-V., van der Wurff‐Jacobs, K. M. G., Jahangier, Z. N., Willis, C. R., Bijlsma, J. W. J., & Lafeber, F. P. J. G. (2009) · Arthritis & Rheumatism · doi:10.1002/art.24754 · Cited by 80 · see citing works
Seronegative rheumatoid arthritis: pathogenetic and therapeutic aspects.
Pratt, A., & Isaacs, J. (2014) · Baillière's Best Practice & Research : Clinical Rheumatology · doi:10.1016/j.berh.2014.10.016 · Cited by 78 · see citing works
Temporal Expression of Growth Factors Triggered by Epiregulin Regulates Inflammation Development
Harada, M., Kamimura, D., Arima, Y., Kohsaka, H., Nakatsuji, Y., Nishida, M., Atsumi, T., Meng, J., Bando, H., Singh, R., et al. (2015) · Journal of Immunology · doi:10.4049/jimmunol.1400562 · Cited by 72 · see citing works
“As these mice age, they spontaneously develop an MHC class II–associated, IL-6–dependent joint disease (F759 arthritis) that resembles RA (8, 14).”
BackgroundSelf-citationNoguchi, D., Wakita, D., Tajima, M., Ashino, S., Iwakura, Y., Zhang, Y., Chamoto, K., Kitamura, H., & Nishimura, T. (2007) · International Immunology · doi:10.1093/intimm/dxm114 · Cited by 76 · see citing works
Anderson, A. E., Pratt, A. G., Sedhom, M. A. K., Doran, J. P., Routledge, C., Hargreaves, B., Brown, P. M., Cao, K. L., Isaacs, J. D., & Thomas, R. (2015) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2014-205850 · Cited by 71 · see citing works
The Pathological and Physiological Roles of IL-6 Amplifier Activation
Murakami, M., & Hirano, T. (2012) · International Journal on Biological Sciences · doi:10.7150/ijbs.4828 · Cited by 69 · see citing works
“CD4-deficient F759 mice alone attenuated disease development [18].”
BackgroundInfluentialSelf-citationKhiong, K., Murakami, M., Kitabayashi, C., Ueda, N., Sawa, S.-I., Sakamoto, A., Kotzin, B., Rozzo, S., Ishihara, K., Verella-Garcia, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30513 · Cited by 82 · see citing works
“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).”
BackgroundMethodSelf-citationLee, J., Nakagiri, T., Oto, T., Harada, M., Morii, E., Shintani, Y., Inoue, M., Iwakura, Y., Miyoshi, S., Okumura, M., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103613 · Cited by 72 · see citing works
Self-citationIL-17-producing T cells can augment autoantibody-induced arthritis
Jacobs, J. P., Wu, H.-J. J., Benoist, C. O., & Mathis, D. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912152106 · Cited by 70 · see citing works
CD4+CD25+regulatory T cells in autoimmune arthritis
Oh, S. A., Rankin, A. L., & Caton, A. J. (2009) · Immunological Reviews · doi:10.1111/j.0105-2896.2009.00848.x · Cited by 65 · see citing works
Lessons from animal models of arthritis over the past decade
Berg, W. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2803 · Cited by 65 · see citing works
Oh, H., Yu, C., Lee, Y., Chan, C., Maminishkis, A., & Egwuagu, C. E. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1004019 · Cited by 64 · see citing works
“have implicated STAT3 and osteopontin in rheumatoid arthritis (28, 29).”
BackgroundLymphopenia, Lymphopenia-Induced Proliferation, and Autoimmunity
Sheu, T.-T., & Chiang, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084152 · Cited by 63 · see citing works
Conditional gp130 deficient mouse mutants
Fasnacht, N., & Müller, W. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.07.001 · Cited by 60 · see citing works
Alves, C. H., Farrell, E., Vis, M., Colin, E. M., & Lubberts, E. (2015) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-015-8522-7 · Cited by 64 · see citing works
“hanced gp130-mediated STAT3 activation and develop lymphocyte-mediated RA-like joint disease [62].”
BackgroundIL-6 positively regulates Foxp3+CD8+ T cells in vivo.
Nakagawa, T., Tsuruoka, M., Ogura, H., Okuyama, Y., Arima, Y., Hirano, T., & Murakami, M. (2010) · International Immunology · doi:10.1093/intimm/dxp119 · Cited by 69 · see citing works
Self-citationBikker, A., Kruize, A. A., Wenting, M. J. G., Versnel, M. A., Bijlsma, J. W. J., Lafeber, F. P. J. G., & van Roon, J. A. G. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-200744 · Cited by 58 · see citing works
Ponchel, F., Cuthbert, R. J., & Goëb, V. (2010) · Clinica Chimica Acta · doi:10.1016/j.cca.2010.09.002 · Cited by 54 · see citing works
Murakami, M., & Hirano, T. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00022 · Cited by 53 · see citing works
“chronic inflammations in tissue-specific MHC class”
InfluentialSelf-citationKDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR
Kamimura, D., Katsunuma, K., Arima, Y., Atsumi, T., Jiang, J., Bando, H., Meng, J., Sabharwal, L., Štofková, A., Nishikawa, N., et al. (2015) · Nature Communications · doi:10.1038/ncomms8474 · Cited by 51 · see citing works
Self-citationHumann, J., Bjordahl, R., Andreasen, K., & Lenz, L. L. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.4.2407 · Cited by 50 · see citing works
“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.”
BackgroundTh17 in Animal Models of Rheumatoid Arthritis
Hashimoto, M. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6070073 · Cited by 48 · see citing works
“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 · see citing works
Interleukin-7 Links T Lymphocyte and Intestinal Epithelial Cell Homeostasis
Shalapour, S., Deiser, K., Kühl, A. A., Glauben, R., Krug, S. M., Fischer, A., Sercan-Alp, Ö., Chappaz, S., Bereswill, S., Heimesaat, M. M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031939 · Cited by 46 · see citing works
“tion in the intestine and other organs [8-10].”
BackgroundYeo, K. P., & Angeli, V. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00083 · Cited by 48 · see citing works
“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 · see citing works
Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients
Kreft, K. L., Verbraak, E., Wierenga‐Wolf, A. F., van Meurs, M., Oostra, B. A., Laman, J. D., & Hintzen, R. Q. (2012) · Genes and Immunity · doi:10.1038/gene.2012.34 · Cited by 46 · see citing works
Valencia, J. C., Egbukichi, N., & Erwin-Cohen, R. A. (2018) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2018.0060 · Cited by 47 · see citing works
Matsuda, K., Shiba, N. N., & Hiraoka, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065173 · Cited by 48 · see citing works
“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., Übner, T., Munday, D. C., Nevels, M., & Paulus, C. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005748 · Cited by 44 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 43 · see citing works
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 · see citing works
“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.-J., Arima, Y., Kamimura, D., Onodera, T., Iwasaki, N., & Murakami, M. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41182 · Cited by 28 · see citing works
“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 · see citing works
Self-citationSabharwal, L., Kamimura, D., Meng, J., Bando, H., Ogura, H., Nakayama, C., Jiang, J., Kumai, N., Suzuki, H., Atsumi, T., et al. (2014) · The Journal of Biochemistry · doi:10.1093/jb/mvu057 · Cited by 34 · see citing works
“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 34 · see citing works
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 · see citing works
“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 · see citing works
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 31 · see citing works
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 · see citing works
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 28 · see citing works
Recent advances in neutralizing the IL-6 pathway in arthritis
Malemud, C. J. (2009) · Open Access Rheumatology Research and Reviews · doi:10.2147/oarrr.s6266 · Cited by 27 · see citing works
“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.”
Mu, H., Hasebe, A., Schelt, A. V., & Cole, B. C. (2010) · Cellular Microbiology · doi:10.1111/j.1462-5822.2010.01540.x · Cited by 25 · see citing works
“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 24 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
“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.”
BackgroundSelf-citationAlshubaily, F. A., & Jambi, E. J. (2022) · Polymers · doi:10.3390/polym14193972 · Cited by 22 · see citing works
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 21 · see citing works
The Discovery of Novel Experimental Therapies for Inflammatory Arthritis
Malemud, C. J. (2009) · Mediators of Inflammation · doi:10.1155/2009/698769 · Cited by 21 · see citing works
“[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 · see citing works
Jin, J., & Yu, Q. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0712360 · Cited by 18 · see citing works
“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 · see citing works
“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 · see citing works
- 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
- Health Sciences › Medicine › Oncology › 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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