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Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis

Nature Medicine volume 11, pages 892–898 (2005)Cite this article

Abstract

Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins. But acute inflammation can occur after exposure to pathogen-derived inducers staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS), or the lectin concanavalin A (ConA), suggesting that physiologic levels of SOCS3 are insufficient to stem proinflammatory signaling under pathogenic circumstances. To test this hypothesis, we developed recombinant cell-penetrating forms of SOCS3 (CP-SOCS3) for intracellular delivery to counteract SEB-, LPS- and ConA-induced inflammation. We found that CP-SOCS3 was distributed in multiple organs within 2 h and persisted for at least 8 h in leukocytes and lymphocytes. CP-SOCS3 protected animals from lethal effects of SEB and LPS by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. It also reduced ConA-induced liver apoptosis. Thus, replenishing the intracellular stores of SOCS3 with CP-SOCS3 effectively suppresses the devastating effects of acute inflammation.

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Figure 1: Structure, design, expression, purification, intracellular delivery and inhibitory activity of recombinant SOCS3 proteins.
Figure 2: In vivo delivery, intracellular persistence and tissue distribution of the CP-SOCS3 proteins.
Figure 3: CP-SOCS3 proteins inhibit the production of inflammatory cytokines IL-6 and TNF-α, and the cell-surface expression of MHC class II in vivo.
Figure 4: Therapeutic effects of CP-SOCS3 in SEB-, LPS-, and ConA-induced inflammatory liver injury.

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Acknowledgements

We thank D. Ballard and E. Ruley for critical reading the manuscript, X.-Y. Liu for experimental advice, M. Shong (Chungnam National University, Korea) for providing mouse SOCS3 cDNA with permission from D. J. Hilton (Royal Melbourne Hospital, Australia). We also thank A. M. Hernandez and K. Quarry for assistance in preparation of the manuscript. US National Institutes of Health grants HL 69542, HL 62356 and HL 68744 supported this work. The use of core facilities in this study was supported by US National Institutes of Health 2P30 CA 68485 to the Vanderbilt Ingram Cancer Center and by 5P30DK058404 to the Vanderbilt Digestive Disease Research Center.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, A-5321 MCN, Nashville, 37232, Tennessee, USA

    Daewoong Jo, Danya Liu, Shan Yao & Jacek Hawiger

  2. Department of Pathology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, A-5321 MCN, Nashville, 37232, Tennessee, USA

    Robert D Collins

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  1. Daewoong Jo
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Correspondence to Jacek Hawiger.

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Supplementary Table 1

In vivo delivery of CP-SOCS3 to immune cells. (PDF 750 kb)

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Jo, D., Liu, D., Yao, S. et al. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med 11, 892–898 (2005). https://doi.org/10.1038/nm1269

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