IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages

Hideo Yasukawa; Masanobu Ohishi; Hiroyuki Mori; Masaaki Murakami; Takatoshi Chinen; Daisuke Aki; Toshikatsu Hanada; Kiyoshi Takeda; Shizuo Akira; Masahiko Hoshijima; Toshio Hirano; Kenneth R. Chien; Akihiko Yoshimura

doi:10.1038/ni938

IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages

Hideo Yasukawa, Masanobu Ohishi, Hiroyuki Mori, Masaaki Murakami, Takatoshi Chinen, Daisuke Aki, Toshikatsu Hanada, Kiyoshi Takeda, Shizuo Akira, Masahiko Hoshijima, Toshio Hirano, Kenneth R. Chien, Akihiko Yoshimura

Internal Medicine

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

641 Citations (Scopus)

Abstract

Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.

Original language	English
Pages (from-to)	551-556
Number of pages	6
Journal	Nature Immunology
Volume	4
Issue number	6
DOIs	https://doi.org/10.1038/ni938
Publication status	Published - Jun 1 2003

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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10.1038/ni938

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title = "IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages",

abstract = "Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.",

author = "Hideo Yasukawa and Masanobu Ohishi and Hiroyuki Mori and Masaaki Murakami and Takatoshi Chinen and Daisuke Aki and Toshikatsu Hanada and Kiyoshi Takeda and Shizuo Akira and Masahiko Hoshijima and Toshio Hirano and Chien, {Kenneth R.} and Akihiko Yoshimura",

note = "Funding Information: We thank Y. Kawabata, J. Anderson and S. Woodard for technical assistance; M. Ohara for language assistance; N. Arifuku for preparing the manuscript; S. Evans for critical comments; I. F{\"o}rster for LysM-cre mice; and A. Mui for the murine IL-10 receptor cDNA in pMX. This work was supported by Grants-in-Aid (to Y.A.) from the Ministry of Education, Science, Technology, Sports and Culture of Japan, the Japan Health Science Foundation, the Human Frontier Science Program, Mochida Memorial Foundation, Uehara Memorial Foundation and the Japan Research Foundation for Clinical Pharmacology.",

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AU - Yasukawa, Hideo

AU - Ohishi, Masanobu

AU - Mori, Hiroyuki

AU - Murakami, Masaaki

AU - Chinen, Takatoshi

AU - Aki, Daisuke

AU - Hanada, Toshikatsu

AU - Takeda, Kiyoshi

AU - Akira, Shizuo

AU - Hoshijima, Masahiko

AU - Hirano, Toshio

AU - Chien, Kenneth R.

AU - Yoshimura, Akihiko

N1 - Funding Information: We thank Y. Kawabata, J. Anderson and S. Woodard for technical assistance; M. Ohara for language assistance; N. Arifuku for preparing the manuscript; S. Evans for critical comments; I. Förster for LysM-cre mice; and A. Mui for the murine IL-10 receptor cDNA in pMX. This work was supported by Grants-in-Aid (to Y.A.) from the Ministry of Education, Science, Technology, Sports and Culture of Japan, the Japan Health Science Foundation, the Human Frontier Science Program, Mochida Memorial Foundation, Uehara Memorial Foundation and the Japan Research Foundation for Clinical Pharmacology.

PY - 2003/6/1

Y1 - 2003/6/1

N2 - Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.

AB - Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.

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IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages

Abstract

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