Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice

Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice

^*Department of Medicine III, Osaka University Medical School, 2–2, Yamada-Oka, Suita, Osaka 565-0871, Japan; ^†Department of Cell Biology and Anatomy I, Osaka University Medical School, 2-2, Yamada-Oka, Suita, Osaka 565-0871, Japan; ^‡Department of Immunology, Research Institute, Osaka Medical Center for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan; and ^§Osaka University, 1-1, Yamada-Oka, Suita, Osaka 565-0871, Japan

Contributed by Tadamitsu Kishimoto

Abstract

Growth, differentiation, and programmed cell death (apoptosis) are mainly controlled by cytokines. The Janus kinase–signal transducers and activators of transcription (JAK-STAT) signal pathway is an important component of cytokine signaling. We have previously shown that STAT3 induces a molecule designated as SSI-1, which inhibits STAT3 functions. To clarify the physiological roles of SSI-1 in vivo, we generated, here, mice lacking SSI-1. These SSI-1−/− mice displayed growth retardation and died within 3 weeks after birth. Lymphocytes in the thymus and spleen of the SSI-1−/− mice exhibited accelerated apoptosis with aging, and their number was 20–25% of that in SSI-1+/+ mice at 10 days of age. However, the differentiation of lymphocytes lacking SSI-1 appeared to be normal. Among various pro- and anti-apoptotic molecules examined, an up-regulation of Bax was found in lymphocytes of the spleen and thymus of SSI-1−/− mice. These findings suggest that SSI-1 prevents apoptosis by inhibiting the expression of Bax.

Footnotes

↵ ¶ To whom reprint requests should be addressed. e-mail: kishimot{at}imed3.med.osaka-u.ac.jp.
ABBREVIATIONS:

STAT,

signal transducers and activators of transcription;

SSI-1,

STAT-induced STAT inhibitor-1;

SOCS-1,

supressor of cytokine signaling;

JAB,

Jak-binding protein;

Bax,

Bcl-2-associated X protein;

Bcl-2,

B cell lymphoma/leukemia-2;

JAK,

Janus kinase;

IL,

interleukin;

INF,

interferon;

TUNEL,

terminal deoxynucleotidyltransferase-mediated UTP end labeling;

Ab,

antibody