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A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis
Open accessAbstract
We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130F759/F759). The gp130F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.
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“On the other hand, the enhancement of IL-6–STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice (41, 63, 66).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [63]
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IL-6 as a keystone cytokine in health and disease
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“This is surprising, because IL-6 has been considered to be an inflammatory cytokine and is implicated in autoimmune diseases and inflammation (33, 55, 56).”
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“sIL-6R binds to IL-6 with comparable affinity as the mbIL-6R (21); consequently, the complex of IL-6/sIL-6R can activate gp130, a membrane protein is ubiquitously expressed (22–25).”
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IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation
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“Indeed, development of autoimmune arthritis in mice possessing a mutated gp130 subunit has been related to the inability of the T cell population to undergo apoptosisinduced cell death (50).”
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Jones, S. A., Richards, P. J., Scheller, J., & Rose‐John, S. (2005) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2005.25.241 · Cited by 254
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“In more chronic conditions such as hepatitis, inflammatory bowel disease, and arthritis, however, characterized by activated T cell infiltration, the balance of STAT1 and STAT3 signaling (presumably controlled by local IL-6 and IFN-γ levels) contributes directly to disease progression (41, 42, 47).”
BackgroundIL-6 signal transduction and its physiological roles: the signal orchestration model
Kamimura, D., Ishihara, K., & Hirano, T. (2003) · Reviews of Physiology, Biochemistry and Pharmacology · doi:10.1007/s10254-003-0012-2 · Cited by 673
“To our knowledge, this is the first and only direct evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease (Atsumi et al. 2002).”
BackgroundSelf-citationNishihara, M., Ogura, H., Ueda, N., Tsuruoka, M., Kitabayashi, C., Tsuji, F., Aono, H., Ishihara, K., Huseby, E., Betz, U. A. K., et al. (2007) · International Immunology · doi:10.1093/intimm/dxm045 · Cited by 268
Self-citationCells of the synovium in rheumatoid arthritis. T lymphocytes.
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Interleukin-6 in rheumatoid arthritis
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“Conversely, gp130 Y759 mutant mice, which have sustained signaling through gp130, develop autoimmune arthritis spontaneously, characterized by accumulation of activated T cells and myeloid cells, which is dependent on IL-6 and STAT3 [162, 163].”
BackgroundTargeting Interleukin-6: All the Way to Treat Autoimmune and Inflammatory Diseases
Tanaka, T., & Kishimoto, T. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4666 · Cited by 255
“For example, IL-6 blockade strategy demonstrably limited susceptibility to Castleman’s disease-like symptoms in IL-6 transgenic mice [35], as well as in various mouse models of rheumatoid arthritis [36-48], systemic lupus erythematosus [49-51], scleroderma [52, 53], C-peptide-induced myositis [54], experimental autoim…”
BackgroundUps and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling
Regis, G., Pensa, S., Boselli, D., Novelli, F., & Poli, V. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.06.004 · Cited by 241
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“In addition to the significant postinjection pain reported after intra-articular LR-PRP treatment,(22) it is established that these cytokines incite and perpetuate inflammation and contribute to subsequent cartilage degradation(5,40) and, most significantly, that overexpression of TNF-a, IL-1b, and IL-6 is sufficient…”
BackgroundThe SH2 domain: versatile signaling module and pharmaceutical target
Kazuya, M., & Mayer, B. J. (2004) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2004.10.005 · Cited by 213
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“However, we recently showed that excessive IL-7 production in nonhematopoietic cells from F759 mutant mice, which show augmented IL-6-gp130-STAT3 signaling, contributes to the development of autoimmune arthritis (Atsumi et al., 2002; Sawa et al., 2006).”
BackgroundSelf-citationDimitriou, I. D., Clemenza, L., Scotter, A. J., Chen, G., Guerra, F. M., & Rottapel, R. K. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00659.x · Cited by 182
“Curiously, mice with mutated gp130 (Y757F), which prevents SOCS3 binding, develop a spontaneous RA-like phenotype (97).”
BackgroundInhibition of IL-6 for the treatment of inflammatory diseases
NISHIMOTO, N. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.03.005 · Cited by 200
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“But how does the Th17 shift occur? (3) Is Stat3 activation also involved in the development of arthritis in psoriatic patients? It was shown that knockin mice with a mutation gp130, in which Stat3 signaling was excessive under the gp130, spontaneously developed arthritis [69].”
BackgroundA genetics-led approach defines the drug target landscape of 30 immune-related traits
Fang, H., Wolf, H. D., Knezevic, B., Burnham, K. L., Osgood, J. A., Sanniti, A., Lara, A. L., Kasela, S., Cesco, S. D., Wegner, J. K., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0456-1 · Cited by 214
Suppression of cytokine signaling: The SOCS perspective
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“Consistent with this, aging gp130 mice are prone to spontaneously develop arthritis [40].”
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“gp130 and gp130 mice that were backcrossed eight times to the C57BL/6 background were used [15].”
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“To investigate the in vivo function of these signaling pathways, we have established a series of knockin mice (27) and shown that one of these lines, gp130F759/F759 (F759), spontaneously develops an RA-like disease in a manner dependent on mature lymphocytes 1 yr after birth (28).”
BackgroundMethodInfluentialSelf-citationNegative regulation of cytokine signaling and immune responses by SOCS proteins.
Yoshimura, A., Nishinakamura, H., Matsumura, Y., & Hanada, T. (2005) · Arthritis Research · doi:10.1186/ar1741 · Cited by 165
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Self-citationCadherin-11 regulates fibroblast inflammation
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“While gp130 mice undergo a spontaneous lymphocyte-mediated rheumatoid arthritis-like joint disease (202), gp130 mice develop gastric tumours (203).”
BackgroundFibroblast‐like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin‐11
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“ing downstream signals resulting from a point mutation of the gp130 subunit of IL-6R spontaneously developed autoimmune arthritis (39).”
BackgroundDevelopments in the scientific understanding of rheumatoid arthritis
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Negative regulation of cytokine signaling influences inflammation
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“IL-6 has been reported to rescue T cells from apoptosis [67,68], and blockade of sIL-6R signaling in experimental models prevented disease onset by suppressing expression of the antiapoptotic regulators Bcl-xl and Bcl-2 [13].”
BackgroundInflammatory pathways in spondyloarthritis
Hreggvidsdottir, H. S., Noordenbos, T., & Baeten, D. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2013.07.016 · Cited by 134
“…in prolonged STAT3 activation develop RA-like arthritis ccompanied by autoantibody production (Atsumi et al., 2002). eletion of STAT3 binding sites of gp130 results on the other hand n sustained SHP-2/ras/Erk signalling and the mice develop…”
BackgroundThe JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?
Ivashkiv, L. B., & Hu, X. (2003) · Arthritis & Rheumatism · doi:10.1002/art.11095 · Cited by 103
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“Noteworthily, mice lacking gp130-SHP2/Ras/ERK signaling in all cells may develop spontaneous autoimmune arthritis due to excessive activation of the STAT1/3 pathway in nonhematopoietic cells (53).”
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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
“As these mice age, they spontaneously develop an MHC class II-associated, IL-6-dependent, tissue-specific joint disease (F759 arthritis) that resembles rheumatoid arthritis (Atsumi et al., 2002; Sawa et al., 2006).”
BackgroundMethodSelf-citationKomatsu, N., & Takayanagi, H. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00077 · Cited by 104
“…is also supported by T-cell-dependent models such as the SKG mouse, which has a mutation in ZAP70 (Sakaguchi et al., 2003), the F759 mouse with a mutation in the gp130 IL-6 receptor subunit (Atsumi et al., 2002), and the IL-1 receptor antagonist (IL-1Ra)-deficient mouse (Horai et al., 2000).”
Backgroundde Hooge, A. S. K., van de Loo, F. A. J., Koenders, M. I., Bennink, M. B., Arntz, O. J., Kolbe, T., & van den Berg, W. B. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20302 · Cited by 103
Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis
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“In experimental arthritis, gp130-mediated STAT3 signaling exacerbates pathology (Atsumi et al., 2002; Nowell et al., 2009), and synovial tissues containing lymphoid follicles show enhanced STAT3 activity (Sawa et al.”
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
“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).”
Self-citationADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer
Schumacher, N., & Rose‐John, S. (2019) · Cancers · doi:10.3390/cancers11111736 · Cited by 108
“These mice can still activate the STAT1/STAT3 pathway [86,87].”
BackgroundInfluentialKomatsu, N., & Takayanagi, H. (2012) · Advances in immunology · doi:10.1016/b978-0-12-394299-9.00002-3 · Cited by 93
“Arthritis in IL-1Ra-deficient mice (Horai et al., 2004) and F759 mice (Atsumi et al., 2002) is also lymphocyte-mediated, as mice with a RAG-deficient background fail to develop arthritis.”
SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use?
Mahony, R., Ahmed, S., Diskin, C., & Stevenson, N. J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2234-x · Cited by 89
Jenkins, B. J., Roberts, A. W., Greenhill, C., Najdovska, M., Lundgren–May, T., Robb, L. G., Grail, D., & Ernst, M. (2006) · Blood · doi:10.1182/blood-2006-08-040352 · Cited by 91
“By analogy with the lymphoid abnormalities in gp130 mice, which also display elevated STAT3 activity, the abnormal distribution of thymocytes and peripheral T cells in our gp130 mice is likely to result from both impairment of negative selection of immature thymic CD4CD8 T cells and clonal deletion of peripheral T cel…”
BackgroundTargeting IL-17 and Th17 Cells in Rheumatoid Arthritis
Sarkar, S., & Fox, D. A. (2010) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2010.02.006 · Cited by 85
“develop spontaneous arthritis due to prolonged unrestrained stimulation of this receptor.(135) IL-6 is elevated in the synovial fluid and sera of patients with RA, and its level correlates with disease activity.”
Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis
Goff, B. L., Blanchard, F., Berthelot, J., Heymann, D., & Maugars, Y. (2010) · Joint Bone Spine · doi:10.1016/j.jbspin.2010.03.002 · Cited by 91
c-Cbl-Dependent Monoubiquitination and Lysosomal Degradation of gp130
Tanaka, Y., Tanaka, N., Saeki, Y., Tanaka, K., Murakami, M., Hirano, T., Ishii, N., & Sugamura, K. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01784-07 · Cited by 82
“ing human wild-type gp130 (gp130) or a mutant gp130 (gp130) (6), a c-Cbl-deficient (c-Cbl / ) MEF, a wild-type c-Cbl-tranfected c-Cbl / (cCbl) MEF (17), and a retroviral packaging cell line, Phoenix-Ampho (Orbi-”
Self-citationSuppressors of cytokine signaling in health and disease
Tan, J. C., & Rabkin, R. (2005) · Pediatric Nephrology · doi:10.1007/s00467-004-1766-8 · Cited by 80
“For example, mice with mutated gp130, in which the SHP2/SOCS3 binding site was disrupted, developed joint disease similar to rheumatoid arthritis with increased production of Th1type cytokines [58].”
BackgroundFas (CD95)-related apoptosis and rheumatoid arthritis
Peng, S. (2005) · Rheumatology · doi:10.1093/rheumatology/kei113 · Cited by 83
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 94
Self-citationLessons from animal models of arthritis over the past decade
Berg, W. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2803 · Cited by 67
Johnston, J. A., & O’Shea, J. J. (2003) · Nature Immunology · doi:10.1038/ni0603-507 · Cited by 64
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
“As these mice age, they spontaneously develop an MHC class II–associated, IL-6–dependent joint disease (F759 arthritis) that resembles RA (8, 14).”
BackgroundMethodSelf-citationJAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration
Damerau, A., Gaber, T., Ohrndorf, S., & Hoff, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239004 · Cited by 76
Lee, 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
“The F759 mice showed enhanced IL-6 signaling due to a lack of gp130-dependent suppressor of cytokine signaling 3-mediated negative feedback (20).”
BackgroundSelf-citationConditional 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
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
“All F759 mice were found to have a rheumatoid arthritis-like disease at about 12-18 months after birth [19](Figure 1).”
BackgroundSelf-citationIL-6 positively regulates Foxp3+CD8+ T cells in vivo
Nakagawa, T., Tsuruoka, M., Ogura, H., Okuyama, Y., Arima, Y., Hirano, T., & Murakami, M. (2009) · International Immunology · doi:10.1093/intimm/dxp119 · Cited by 62
Self-citationBrender, C., Tannahill, G. M., Jenkins, B. J., Fletcher, J. G., Columbus, R., Saris, C. J. M., Ernst, M., Nicola, N. A., Hilton, D. J., Alexander, W. S., et al. (2007) · Blood · doi:10.1182/blood-2006-08-041541 · Cited by 65
SHP2 forecast for the immune system: fog gradually clearing
Salmond, R. J., & Alexander, D. R. (2006) · Trends in Immunology · doi:10.1016/j.it.2006.01.007 · Cited by 63
Regulation of TLR signaling and inflammation by SOCS family proteins
Yoshimura, A., Ohishi, H. M. M., Aki, D., & Hanada, T. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0403194 · Cited by 66
“For example, a mouse line with a mutated gp130, to which SOCS3 cannot bind, developed a RA-like joint disease with increased production of Th1-type cytokines and Igs of the IgG2a and IgG2b classes [ 58 ].”
BackgroundInterpreting mixed signals: the cell's cytokine conundrum
Delgoffe, G. M., Murray, P. J., & Vignali, D. A. A. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.07.013 · Cited by 69
Nakamura, K., Kouro, T., Kincade, P. W., Malykhin, A., Maeda, K., & Coggeshall, K. M. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031193 · Cited by 53
“Lastly, transgenic animals harboring a Y to F point mutant IL-6 receptor spontaneously develop rheumatoid arthritis (34).”
BackgroundCytokines in the rheumatic diseases.
Arend, W., & Gabay, C. (2004) · Rheumatic Disease Clinics of North America · doi:10.1016/s0889-857x(03)00115-7 · Cited by 65
“Through gp130, IL-6 induces two signal transduction pathways, one of which may be stimulatory to inflammatory responses and the other may be inhibitory [88].”
BackgroundTargeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What’s the Difference?
Avcı, A. B., Feist, E., & Burmester, G. R. (2018) · BioDrugs · doi:10.1007/s40259-018-0320-3 · Cited by 61
Forrai, A., Boyle, K., Hart, A. H., Hartley, L., Rakar, S., Willson, T. A., Simpson, K., Roberts, A. W., Alexander, W. S., Voss, A. K., et al. (2005) · Stem Cells · doi:10.1634/stemcells.2005-0323 · Cited by 65
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“Titers of serum antibodies Rheumatoid factor (RF) for mouse Ig of both IgM and IgG classes, anti-dsDNA antibodies and anti-ssDNA antibodies were measured using commercial ELISA kits (Shibayagi, Japan) as described ( 13 ).”
MethodRaimondo, A., Lembo, S., Caprio, R. D., Donnarumma, G., Monfrecola, G., Balato, N., Ayala, F., & Balato, A. (2017) · European Journal of Immunology · doi:10.1002/eji.201646774 · Cited by 54
Immune-mediated pathways in chronic inflammatory arthritis
Gorman, C., & Cope, A. P. (2008) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2008.01.003 · Cited by 45
Pathophysiological roles for IL-18 in inflammatory arthritis
Matsui, K., Tsutsui, H., & Nakanishi, K. (2003) · Expert opinion on therapeutic targets · doi:10.1517/14728222.7.6.701 · Cited by 54
Murakami, M., & Hirano, T. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00022 · Cited by 53
“As these mice age, they spontaneously develop a RA-like tissue-specific disease, indicating that constitutive activation of IL-6 signaling is involved in the development of certain autoimmune diseases (Atsumi et al., 2002).”
Self-citationPsoriatic 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
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SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling
Niogret, C., Birchmeier, W., & Guarda, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02468 · Cited by 58
Mouse models of psoriasis and their relevance
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Th17 in Animal Models of Rheumatoid Arthritis
Hashimoto, M. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6070073 · Cited by 51
“In gp130 F759/F759 knock-in (gp130 F759) mice, tyrosine 759 (Y759 in human gp130) in the SHP2-binding site of gp130 is replaced with phenylalanine (F) [13].”
Background
Metadata
- Authors
- Atsumi, T., Ishihara, K., Kamimura, D., Ikushima, H., Ohtani, T., Hirota, S., Kobayashi, H., Park, S.-J., Saeki, Y., Kitamura, Y., & Hirano, T.
- Affiliations
- RIKEN (JP)
- The University of Osaka (JP)
- 1Department of Molecular Oncology (C7), Graduate School of Medicine
- 2Department of Pathology (C2), Graduate School of Medicine
- Kowa (Japan) (JP)
- 3Department of Molecular Medicine (C4), Graduate School of Medicine
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2002-09-30
- Volume
- 196
- Issue
- 7
- Pages
- 979-990
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2194024
- OpenAlex
- W2145478309
- Cited by
- 225
- References
- 49
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 13 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 12 · 2014: 10 · 2013: 11 · 2012: 13
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- 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
- gp130, rheumatoid arthritis, autoimmune arthritis, autoantibodies, thymic selection, Fas ligand, activation-induced cell death, STAT3 signaling
- MeSH terms
- Animals, Antibody Formation, Arthritis, Experimental, Base Sequence, Binding Sites, Bone and Bones, Enterotoxins, Lymph Nodes, Mice, Inbred C57BL, Mice, Transgenic, Staphylococcus aureus, T-Lymphocytes, Tyrosine, CD4-Positive T-Lymphocytes, Polymerase Chain Reaction, Apoptosis, Point Mutation, DNA Primers, Superantigens, Amino Acid Substitution, Receptors, Interleukin-6, Protein Subunits, Mice
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