The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis
Abstract
Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.
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F759 arthritis is enhanced by the HTLV-1 pX gene, which encodes Tax, a transcriptional trans-activator of NF-κB, showing the synergistic effect of STAT3 and NF-κB.
“Furthermore, F759 arthritis is enhanced by human T-cell lymphotropic virus 1 (HTLV-1) pX gene, which encodes Tax, a transcriptional trans-activator of NF-κB, showing the synergistic effect of STAT3 and NF-κB (255).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [255]
Cites
Hirano, T., Taga, T., Yasukawa, K., Nakajima, K., Nakano, N., Takatsuki, F., Shimizu, M., Murashima, A., Tsunasawa, S., & Sakiyama, F. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.1.228 · Cited by 351 · see citing works
Atsumi, 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
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IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“Furthermore, F759 arthritis is enhanced by human T-cell lymphotropic virus 1 (HTLV-1) pX gene, which encodes Tax, a transcriptional trans-activator of NF-κ B, showing the synergistic effect of STAT3 and NF-κ B (255).”
BackgroundSawa, S.-I., Kamimura, D., Jin, G.-H., Morikawa, H., Kamon, H., Nishihara, M., Ishihara, K., Murakami, M., & Hirano, T. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052187 · Cited by 176 · see citing works
Self-citationDisease-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
“Clinical Assessment of Arthritis Mice were inspected and assessed for signs of arthritis as described previously (Atsumi et al., 2002; Ishihara et al., 2004; Murakami et al., 2011; Ogura et al., 2008; Sawa et al., 2006).”
MethodMurakami, 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
“Indeed, forced expression of p40 Tax in F759 mice has been seen to enhance disease development (Ishihara et al., 2004).”
Self-citationMurakami, M., & Hirano, T. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00022 · Cited by 53 · see citing works
“The number of cytokine-secreting effector/memory CD4+ T cells increases with age due to an accumulation of pathogen-specific memory T cells and homeostatic proliferation of CD4+ T cells.”
- Authors
- Ishihara, K.
- Affiliations
- The University of Osaka (JP)
- Corresponding author
- Ishihara, K.
- ORCID
- Ishihara, K.
- Venue
- International Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-03-01
- Volume
- 16
- Issue
- 3
- Pages
- 455-465
- ISSN
- 0953-8178 (ISSN-L)
- 1460-2377
- OpenAlex
- W2123253747
- Cited by
- 21
- References
- 2
- Citations by year
- 2026: 1 · 2024: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- rheumatoid arthritis, gp130, autoimmunity, splenomegaly, hypergammaglobulinemia, autoantibodies, T cell activation, granulocytes, MHC class II, genetic susceptibility
- MeSH terms
- Animals, Ankle Joint, Arthritis, Rheumatoid, Disease Models, Animal, Flow Cytometry, Lymph Nodes, Membrane Glycoproteins, Mice, Inbred C57BL, Radiography, Spleen, Tyrosine, Human T-lymphotropic virus 1, Antigens, CD, Interleukin-6, T-Lymphocyte Subsets, Genes, pX, Point Mutation, Myeloid Cells, Cytokine Receptor gp130, Mice
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