Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor α-induced cell death in fibroblasts

Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor α-induced cell death in fibroblasts

Departments of ^*Medicine III, ^‡Microbiology, and ^§Genetics, Osaka University Medical School, 2-2, Yamada-oka, Suita-city, Osaka 565-0871, Japan; ^¶Osaka University, 1-1 Yamada-oka, Suita-city, Osaka 565-0871, Japan; and ^†Department of Immunology and Inflammation Medicinal Biology Research Laboratory, Fujisawa Pharmaceutical Company, Ltd., 1-6 Kashima 2 Chome Yodogawa-ku, Osaka 532-8514, Japan

Contributed by Tadamitsu Kishimoto

Abstract

Signal transducers and activators of transcription (STAT)-induced STAT inhibitor-1 [SSI-1; also known as suppressor of cytokine signaling-1 (SOCS-1)] was identified as a negative feedback regulator of Janus kinase-STAT signaling. We previously generated mice lacking the SSI-1 gene (SSI-1 −/−) and showed that thymocytes and splenocytes in SSI-1 −/− mice underwent accelerated apoptosis. In this paper, we show that murine embryonic fibroblasts lacking the SSI-1 gene are more sensitive than their littermate controls to tumor necrosis factor-α (TNF-α)-induced cell death. In addition, L929 cells forced to express SSI-1 (L929/SSI-1), but not SSI-3 or SOCS-5, are resistant to TNF-α-induced cell death. Furthermore L929/SSI-1 cells treated with TNF-α sustain the activation of p38 mitogen-activated protein (MAP) kinase. In contrast, SSI-1 −/− murine embryonic fibroblasts treated with TNF-α show hardly any activation of p38 MAP kinase. These findings suggest that SSI-1 suppresses TNF-α-induced cell death, which is mediated by p38 MAP kinase signaling.

Footnotes

↵ ‖ To whom reprint requests should be sent at ^¶ address. E-mail: kishimot{at}imed3.med.osaka-u.ac.jp.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.090084797.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.090084797
Abbreviations:

STAT,

signal transducers and activators of transcription;

SSI-1,

STAT-induced STAT inhibitor-1;

SOCS-1,

suppressor of cytokine signaling-1;

TNF-α,

tumor necrosis factor-α;

JAK,

Janus kinase;

MEFs,

murine embryonic fibroblasts;

RQ,

an Arg-105 point mutation of SSI-1 yielding Gln;

TRAF,

TNF receptor-associated factor;

MAP kinase,

mitogen-activated protein kinase;

MKK,

MAP kinase kinase;

ERK,

extracellular signal-regulated kinase;

JNK,

c-Jun amino-terminal kinase;

ATF2,

activating transcription factor 2;

WST-8,

2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium;

1-methoxy-PMS,

1-methoxyphenazine methosulfate