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Departments of
*
Medicine III and
Microbiology,
Osaka University Medical School;
§
Biomolecular Engineering Research Institute; and
¶
Osaka University, Suita City, Osaka, Japan
Previous experiments have shown that STAT-induced STAT inhibitor-1
(SSI-1; also named suppressors of cytokine signaling-1 (SOCS-1) or
Janus kinase binding protein) is predominantly expressed in lymphoid
organs and functions in vitro as a negative regulator of cytokine
signaling. To determine the function of SOCS-1 in vivo, we generated
SSI-1 transgenic mice using the lck proximal promoter
that drives transgene expression in T cell lineage. In thymocytes
expressing SSI-1 transgene, tyrosine phosphorylation of STATs in
response to cytokines such as IFN-
, IL-6, and IL-7 was inhibited,
suggesting that SSI-1 suppresses cytokine signaling in primary
lymphocytes. In addition, lck-SSI-1 transgenic mice
showed a reduction in the number of thymocytes as a result of the
developmental blocking during triple-negative stage. They also
exhibited a relative increase in the percentage of CD4+ T
cells, a reduction in the number of 
T cells, as well as the
spontaneous activation and increased apoptosis of peripheral T cells.
Thus, enforced expression of SSI-1 disturbs the development of
thymocytes and the homeostasis of peripheral T cells. All these
features of lck-SSI-1 transgenic mice strikingly
resemble the phenotype of mice lacking common -chain or Janus
kinase-3, suggesting that transgene-derived SSI-1 inhibits the
functions of common -chain-using cytokines. Taken together, these
results suggest that SSI-1 can also inhibit a wide variety of cytokines
in vivo.
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