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Department of Internal Medicine (E.S.P., H.K., J.M.S., S.J.P.,
Y.K.K., H.K.R., M.S.) Department of Anatomy (O.-Y.K.)
Chungnam National University School of Medicine Taejon, 301–040,
Korea
Department of Internal Medicine (B.Y.C.) Seoul
National University School of Medicine Seoul, 110–744, Korea
Department of Biological Sciences (J.C.) Korea Advanced
Institute of Science and Technology Taejon 305–701, Korea
TSH has multiple physiological roles: it is
required for growth, differentiation, and function of the thyroid
gland, and it regulates transcription of interferon-
(IFN-)-responsive genes in thyrocytes, including genes for the major
histocompatibility complex and intercellular adhesion molecule-1. This
report demonstrates that TSH induces the expression of suppressor of
cytokine signaling (SOCS)-1 and -3 proteins and alters the
phosphorylation state of signal transducer and activator of
transcription (STAT) proteins STAT1 and STAT3. The expression of SOCS-1
and SOCS-3 and the phosphorylation state of STAT1 and STAT3 were
examined after treatment with TSH or IFN- in either TSH-sensitive
FRTL-5 thyroid cells or TSH-insensitive FRT and buffalo rat liver (BRL)
cells, which lack functional TSH receptors. SOCS-1 and SOCS-3 are
constitutively expressed in FRTL-5 cells, but not in FRT and BRL cells.
IFN- up-regulated SOCS-1 and SOCS-3 RNA and protein in FRTL-5 cells,
as reported previously for nonthyroid cells. Interestingly, TSH
also significantly induced SOCS-1 and SOCS-3 in FRTL-5 cells, but not
in FRT and BRL cells. When SOCS-1 or SOCS-3 was overexpressed in FRTL-5
cells, STAT1 phosphorylation at Y701 and STAT1/DNA complex formation in
response to IFN- were reduced. Furthermore, overexpression of either
SOCS-1 or SOCS-3 significantly inhibited the IFN--mediated
transactivation of the rat ICAM-1 (intercellular adhesion molecule-1)
promoter. TSH and IFN- had different effects on STAT1 and STAT3
phosphorylation. The phosphorylation of Y701 in STAT1, which is
responsible for homodimer formation, nuclear translocation, and DNA
binding, was specifically stimulated by IFN-, but not by TSH or
forskolin. However, the phosphorylation of S727 in STAT1 was induced by
IFN-, TSH, and forskolin. TSH induced phosphorylation of both Y705
and S727 in STAT3, while IFN- phosphorylated only the Y705. In
addition, we found that SOCS-3 was associated with JAK1 and JAK2 and
that these associations were stimulated by TSH. These findings
demonstrate that TSH induces SOCS in thyroid cells and provides the
evidence of signal cross-talk between TSH and cytokines in thyroid
cells.
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