Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction

Ogura, Hideki; Murakami, Masaaki; Okuyama, Yuko; Tsuruoka, Mineko; Kitabayashi, Chika; Kanamoto, Minoru; Nishihara, Mika; Iwakura, Yoichiro; Hirano, Toshio

doi:10.1016/j.immuni.2008.07.018

Cited by 564Psoriasis: Treatment and PathogenesisCytokine Signaling Pathways and InteractionsRheumatoid Arthritis Research and Therapies

Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction

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Ogura, Hideki, Murakami, Masaaki, Okuyama, Yuko, Tsuruoka, Mineko, Kitabayashi, Chika, Kanamoto, Minoru, Nishihara, Mika, Iwakura, Yoichiro +1 more·2008·Immunity

DOI 10.1016/j.immuni.2008.07.018

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Abstract

Dysregulated cytokine expression and signaling are major contributors to a number of autoimmune diseases. Interleukin-17A (IL-17A) and IL-6 are important in many disorders characterized by immune self-recognition, and IL-6 is known to induce the differentiation of T helper 17 (Th17) cells. Here we described an IL-17A-triggered positive-feedback loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription 3 (STAT3) in fibroblasts. Importantly, enhancement of this loop caused by disruption of suppressor of cytokine signaling 3 (SOCS3)-dependent negative regulation of the IL-6 signal transducer gp130 contributed to the development of arthritis. Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases.

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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 [66]
The Introduction and Discussion link IL-6 signaling in fibroblasts to F759 arthritis, and the EAE experiments report that disrupting IL-6–STAT3 signaling in type I collagen-positive cells attenuated Th17-cell-mediated EAE. Our copy does not establish that IL-6 together with soluble IL-6Rα acts on endothelial cells to recruit Th17 cells; it reports soluble IL-6R measurement, not that recruitment mechanism. (LLM, conf=0.85)
Experimental — accuracy not yet measured
IL-6 and IL-17 or TNFα synergistically enhance the production of various pro-inflammatory mediators including IL-6 from non-immune cells in a manner dependent on STAT3 and NF-κB.
“Furthermore, IL-6 and IL-17 or TNFα synergistically enhance the production of various pro-inflammatory mediators including IL-6 from non-immune cells in a manner dependent on STAT3 and NF-κB (66).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [66]
The Discussion reports that IL-17A and IL-6 synergistically increased IL-6 and other inflammatory mediators in mouse embryonic fibroblasts through NF-κB and STAT3 signaling. The paper only suggests that TNF-α may enhance the IL-6 amplifier; it does not establish the claimed IL-6–TNF-α synergy or its dependence on those pathways. (LLM, conf=0.89)
Experimental — accuracy not yet measured
F759 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 [66]
The Discussion reports that F759 arthritis is dependent on IL-17A: deleting IL-17A significantly reduced arthritis scores, and overexpressing it induced arthritis. The paper also reports increased Th17 cells in older F759 mice, but these findings do not establish that Th17 cells themselves are required for arthritis development. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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 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 [66]
The Introduction (page unavailable) says the F759 mutation in nonhematopoietic cells is essential for CD4+ T-cell homeostatic proliferation and arthritis development. The paper also reports increased IL-6 and the chemokine KC in F759 fibroblasts, and more Th17 cells in older F759 mice, but it does not establish that this production is necessary for Th17 accumulation in the lesion. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The 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 [66]
The Introduction states that the F759 mutation in nonhematopoietic cells is essential for arthritis development and that the mutation is not required in T cells. It does not establish that the mutation is unnecessary in all immune cells, as the claim says. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured

Mice devoid of STAT3 or gp130 in non-immune cells like type-1 collagen positive cells are highly resistant to F759 arthritis and EAE.
“Consistent with the concept that IL-6 Amp activation in non-immune cells plays a pivotal role in the development of autoimmune diseases, mice devoid of STAT3 or gp130 in non-immune cells like type-1 collagen positive cells are highly resistant to F759 arthritis and EAE (54, 66).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [66]
The Discussion (page unavailable) reports that deleting STAT3 in type I collagen-positive fibroblasts suppressed arthritis in F759 mice. The EAE passage (page unavailable) reports at least partial suppression after STAT3 deletion, but in a Th17-transfer model using otherwise wild-type mice. The paper does not show gp130 deletion in those cells or establish that the mice were highly resistant to both diseases. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Amplification of the IL-6-STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-κB activators during inflammation.
“Therefore, amplification of the IL-6–STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-κB activators during inflammation processes (Fig. 3) (41, 66).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [66]
The Discussion reports that IL-17A and IL-6 synergistically increase IL-6 expression through NF-κB and STAT3, establishing a feedback loop. The paper also proposes that other factors may enhance this amplifier, but it does not establish the claimed augmentation by several pathways following induction of other STAT3 and NF-κB activators during inflammation. (LLM, conf=0.83)
Experimental — accuracy not yet measured
An activated IL-6 Amp enhances the production of chemokines to recruit lymphoid cells and myeloid cells including Th17 cells in the lesion, so the IL-6 Amp could be further enhanced.
“Since an activated IL-6 Amp enhances the production of chemokines to recruit lymphoid cells and myeloid cells including Th17 cells in the lesion, the IL-6 Amp could be further enhanced (66).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [66]
The paper reports that IL-17A and IL-6 synergistically increase expression of KC and MIP2 in fibroblasts (results passage labeled Abstract; no page available), and it proposes an IL-6 signaling amplifier involving Th17 cells (Abstract; no page available). It does not establish that these chemokines recruit lymphoid and myeloid cells, including Th17 cells, into lesions or that such recruitment further enhances the amplifier. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Enhancement of IL-6-STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice.
“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 [66]

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“We first investigated the roles of IL-17A and IL-6 signaling in fibroblasts because we previously used chimeric mice with transplanted bone-marrow cells to show that the F759 mutation in nonhematopoietic cells but not in hematopoietic cells results in spontaneous autoimmune arthritis (Sawa et al., 2006).”
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Authors: Ogura, H., Murakami, M., Okuyama, Y., Tsuruoka, M., Kitabayashi, C., Kanamoto, M., Nishihara, M., Iwakura, Y., & Hirano, T.
Affiliations: Japan Science and Technology Agency (JP)
Corresponding author: Hirano, Toshio
ORCID: Ogura, Hideki
Murakami, Masaaki
Okuyama, Yuko
Iwakura, Yoichiro
Venue: Immunity
Publisher: Elsevier BV
Published: 2008-10
Volume: 29
Issue: 4
Pages: 628-636
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2008.07.018
OpenAlex: W1989588757
Cited by: 564
References: 10
Citations by year: 2026: 18 · 2025: 19 · 2024: 23 · 2023: 37 · 2022: 39 · 2021: 36 · 2020: 35 · 2019: 33 · 2018: 33 · 2017: 35 · 2016: 24 · 2015: 31 · 2014: 34 · 2013: 38 · 2012: 37
FWCI: 12.76
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1786 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Immunity (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords: IL-17A, interleukin-6, positive feedback loop, Th17 cells, NF-κB, STAT3, SOCS3, gp130, fibroblasts, arthritis, experimental autoimmune encephalomyelitis, autoimmunity, cytokine signaling
MeSH terms: Suppressor of Cytokine Signaling 3 Protein, Animals, Arthritis, Encephalomyelitis, Autoimmune, Experimental, Fibroblasts, Mice, Inbred C57BL, Mice, Mutant Strains, Signal Transduction, Autoimmunity, Interleukin-6, NF-kappa B, Interleukin-17, Feedback, Physiological, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice

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Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction

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