Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction

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

doi:10.1016/j.immuni.2008.07.018

Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction

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

Research output: Contribution to journal › Article › peer-review

361 Citations (Scopus)

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)-κB 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.

Original language	English
Pages (from-to)	628-636
Number of pages	9
Journal	Immunity
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2008.07.018
Publication status	Published - 2008 Oct 17
Externally published	Yes

Keywords

CELLIMMUNO
MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2008.07.018

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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.

In: Immunity, Vol. 29, No. 4, 17.10.2008, p. 628-636.

Research output: Contribution to journal › Article › peer-review

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title = "Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction",

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)-κB 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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note = "Funding Information: We thank M. Kopf (Max-Planck-Institute of Immunobiology, Germany) for IL-6-deficient mice, G. Karsenty (Baylor College of Medicine, Houston, TX) for type I collagen-Cre mice, S. Akira (Osaka University, Japan) for STAT3 flox/flox mice, and A. Kumanogo (Osaka University, Japan) for kind advice about the induction of EAE. We appreciate the excellent technical assistance provided by J. Jiang, R. Sato, E. Iketani, and T. Hayashi and thank R. Masuda for her excellent secretarial assistance. We thank D. Kamimura for careful reading of this manuscript. This work was supported by KAKENHI (H.O., M.M., and T.H.), Uehara Foundation (M.M.), and the Osaka Foundation for the Promotion of Clinical Immunology (M.M. and T.H.). The authors declare they have no conflicting financial interests. ",

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AU - Tsuruoka, Mineko

AU - Kitabayashi, Chika

AU - Kanamoto, Minoru

AU - Nishihara, Mika

AU - Iwakura, Yoichiro

AU - Hirano, Toshio

N1 - Funding Information: We thank M. Kopf (Max-Planck-Institute of Immunobiology, Germany) for IL-6-deficient mice, G. Karsenty (Baylor College of Medicine, Houston, TX) for type I collagen-Cre mice, S. Akira (Osaka University, Japan) for STAT3 flox/flox mice, and A. Kumanogo (Osaka University, Japan) for kind advice about the induction of EAE. We appreciate the excellent technical assistance provided by J. Jiang, R. Sato, E. Iketani, and T. Hayashi and thank R. Masuda for her excellent secretarial assistance. We thank D. Kamimura for careful reading of this manuscript. This work was supported by KAKENHI (H.O., M.M., and T.H.), Uehara Foundation (M.M.), and the Osaka Foundation for the Promotion of Clinical Immunology (M.M. and T.H.). The authors declare they have no conflicting financial interests.

PY - 2008/10/17

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N2 - 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)-κB 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.

AB - 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)-κB 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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Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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