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

Nature Immunology volume 4, pages 551–556 (2003)Cite this article

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.

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Figure 1: Deletion of Socs3 in macrophages and neutrophils.
Figure 2: IL-6 suppresses LPS-induced TNF and IL-12 production of macrophages in LysM-cre Socs3fl/fl mice.
Figure 3: Sustained activation of STAT3 by IL-6 in Socs3−/− macrophages.
Figure 4: gp130-SOCS3 interaction.
Figure 5: LysM-cre Socs3fl/fl mice are resistant to LPS-induced septic shock.

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Acknowledgements

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.

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Author notes

  1. Hideo Yasukawa

    Present address: Cardiovascular Research Institute and The Third Department of Medicine, Kurume University, 67 Asahi-machi, Kurume, 830-0011, Japan

  2. Hideo Yasukawa, Masanobu Ohishi and Hiroyuki Mori: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Medicine and Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093-0641, California, USA

    Hideo Yasukawa, Masahiko Hoshijima & Kenneth R Chien

  2. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masanobu Ohishi, Hiroyuki Mori, Takatoshi Chinen, Daisuke Aki, Toshikatsu Hanada & Akihiko Yoshimura

  3. Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, 2-2, Yamada-oka Suita, Osaka, 565-0871, Japan

    Masaaki Murakami & Toshio Hirano

  4. Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

    Kiyoshi Takeda & Shizuo Akira

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Correspondence to Akihiko Yoshimura.

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Yasukawa, H., Ohishi, M., Mori, H. et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4, 551–556 (2003). https://doi.org/10.1038/ni938

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