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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3308-3314
gp130, The Cytokine Common Signal-Transducer of Interleukin-6
Cytokine Family, Is Downregulated in T Cells In Vivo by Interleukin-6
By
Xue-Jie Wang,
Tetsuya Taga,
Kanji Yoshida,
Mikiyoshi Saito,
Tadamitsu Kishimoto, and
Hitoshi Kikutani
From the Department of Molecular Immunology, Research Institute for
Microbial Diseases, Osaka University, Osaka, Japan; the Department of
Molecular Cell Biology, Medical Research Institute, Tokyo Medical and
Dental University, Tokyo, Japan; Fuji Gotemba Research Laboratories,
Chugai Pharmaceutical Co, Ltd, Shizuoka, Japan; and the Department of
Medicine III, Osaka University Medical School, Osaka, Japan.
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ABSTRACT |
gp130 is a common signal-transducing receptor component for the
interleukin-6 (IL-6) family of cytokines. To investigate the expression
of gp130 in T-cell subsets and its regulation, anti-murine gp130
monoclonal antibody (MoAb) was used for flow cytometric analysis. In
normal mice, gp130 was differentially expressed in thymocyte and
splenic T-cell subpopulations defined by CD4/CD8 expression. In aged
MRL/lpr mice, although gp130 expression was detectable in
splenic CD4+ or CD8+ T cells, gp130
expression was significantly downregulated. Because serum levels of
IL-6 and soluble IL-6 receptor (sIL-6R) are elevated in these mice, we
examined the possibility that the downregulation of gp130 expression on
splenic T cells might be produced in response to continuous activation
of gp130 by high levels of serum IL-6. In transgenic mice
overexpressing IL-6, gp130 expression in the splenic T cells was
significantly decreased. After stimulation with IL-6 in vitro, the
level of gp130 on CD4+ or CD8+ splenic T
cells from normal mice was significantly decreased. These results
suggest that the expression of gp130 in splenic T cells could be
downregulated by the IL-6 stimulation under physiological or
pathological circumstances.
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INTRODUCTION |
COMMUNICATION BETWEEN cells in immune and
hematopoietic systems is largely mediated by soluble factors called
cytokines.1 gp130 was initially identified as a
signal-transducing receptor component that associates with
interleukin-6 receptor (IL-6R) when the receptor binds
IL-6.2,3 Subsequently, gp130 has been shown to be shared by
multiple cytokines in addition to IL-6, such as receptors for IL-11,
leukemia inhibitory factor (LIF), oncostatin M, ciliary neurotrophic
factor (CNTF), and cardiotrophin-1 (CT-1).4,5
It has been reported that gp130 mRNA is ubiquitously expressed in
almost all the organs examined, including heart, spleen, kidney, lungs,
liver, and brain.6 It has also been shown that the
regulatory mechanism of gp130 expression may be somewhat different from
that of IL-6R on the different cell lines.7-10 For example, IL-6R and gp130 mRNA levels are differentially regulated by IL-6 and by
interferons in multiple myeloma cell lines.10 Other reports show that gp130 transcripts on various cells are upregulated in vitro
by multiple factors, including IL-6.7,8
The existence of common signal transducers has been discovered not only
in the IL-6R system, but in the other cytokine receptor systems as
well. Like gp130, the common  chain and the common  chain are
also shown to be shared with multiple cytokine receptors. The cytokine
receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 use the same
chain as an essential subunit.11 It has been shown that
the common -chain is shared with multiple cytokine receptors for
IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor
(GM-CSF).12 Each cytokine has its own unique functions in
certain cell types, and it has been considered that cellular responsiveness is largely determined by regulated expression of the
ligand-specific receptors.1,4,11,12 Because the expression of common chains is believed to be relatively resistant to regulation, regulation of the common chain expression has been studied
poorly to date. Thus, it would be of interest to examine the protein expression and the regulation of common signal transducer in vivo.
This report shows that with the use of a specific monoclonal antibody
(MoAb) against murine gp130, we have examined the expression of gp130
on T-lineage cells in normal mice and MRL/lpr mice. To understand further the regulatory mechanism of gp130 expression in T
cells by its ligands, we also investigated the expression of gp130 in T
cells stimulated by IL-6 in vitro or those from IL-6 transgenic mice.
Our results suggest that gp130 expression on T cells is downregulated
by IL-6 both in vitro and in vivo.
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MATERIALS AND METHODS |
Animals.
C57BL/6, MRL/lpr, and MRL/n female mice were purchased from
Shizuoka Laboratory Animal Center (Hamamatsu, Japan). IL-6, IL-6R single transgenic mice, and IL-6/IL-6R double transgenic mice were
prepared as previously described.13,14 For these
experiments, 4-month-old transgenic mice of both sexes were used.
Establishment of transfectants.
The murine gp130 cDNA was subcloned at a Xho I site of the
BCMGNeo expression vector, kindly provided by Dr H. Karasuyama as
previously described.15 Rat glioma C6G cells were
transfected with BCMGNeo-containing murine gp130 cDNA. After selection
with 1 mg/mL of the antibiotic G418 (Sigma, St Louis, MO), the
gp130-expressing transfectant C6Gm130 was obtained.
Antibodies.
The preparation of anti-mouse gp130 MoAb (RX19) has been described
elsewhere.16 RX19 and control rat myeloma IgG2a
(Zymed, San Francisco, CA), were labeled with fluorescein
isothiocyanate (FITC) (American Qualex, San Clemente, CA).
Phycoerythrin (PE)-anti-CD4 and Cy-chrome-anti-CD8 were purchased
from Pharmigen (San Diego, CA). PE-anti-B220 and PE-conjugated
streptavidin were obtained from Becton Dickinson (San Jose,
CA).
Preparation of T lymphocytes.
Cells were prepared from the spleen and thymus by passing them through
a mesh. Lymphocytes were separated from murine spleens and thymus with
standard procedures.17 The splenic cells were then labeled
with anti-CD4, anti-CD8, and anti-Thy1.2 MoAb coupled with magnetic
microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany)
for 30 minutes on ice, and then were washed three times with a staining
buffer (phosphate-buffered saline [PBS] containing 0.5% bovine serum
albumin [BSA] and 0.001% sodium azide). The labeled cells were
passed through MACS separation columns placed in the MACS separator
(Miltenyi Biotec), the columns were then washed and
removed from the magnet. The positive cells were washed out and
collected.
Cell cultures and fluorescence-activated cell sorter (FACS)
analysis.
Purified CD4+ or CD8+ splenic cells were
cultured with or without IL-6 in RPMI 1640 supplemented with 10% fetal
calf serum (FCS), penicillin (50 U/mL), streptomycin (50 mg/mL), 50 mmol/L 2-ME at an initial concentration of 5 × 106
cells/mL in 96 round-bottomed well plates at 37°C in a humidified atmosphere with 5% CO2 in the air. After 2 days of
culture, cells were stained with antibodies and analyzed with a FACScan
flow cytometer (Becton Dickinson).
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RESULTS |
Specific recognition of murine gp130 by MoAb RX19.
To examine the specificity of RX19, we used a rat glioma cell line,
C6G, and its transfectant-expressing mouse gp130 (C6Gm130). As shown in
Fig 1, C6Gm130 was positively stained with
RX19, whereas the parent cells showed no staining, suggesting that RX19
specifically recognizes murine gp130. To analyze the expression of
gp130 in lymphocytes freshly prepared from mice, we had to exclude the possibility that recognition of gp130 by RX19 might be influenced by
the IL-6/IL-6R complex, which binds to gp130. RX19 was used for
staining thymocytes, preincubated with or without an excess amount of
IL-6 and sIL-6R and then analyzed by FACS. As shown in Fig
2, the fluorescence intensity of cells
stained by RX19 was not affected by 20-minute preincubation with IL-6
and sIL-6R, indicating that RX19 recognizes the epitope on gp130 as
distinct from the IL-6R-binding site.
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| Fig 1.
Specific recognition of murine gp130 by MoAb RX19. C6G
cells and their transfectants with murine gp130 cDNA (C6Gm130 cells) were used. Closed and open histograms show the staining with RX19 and
control rat myeloma IgG2a, respectively.
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| Fig 2.
Recognition of murine gp130 by MoAb RX19 was not
inhibited by the complex of IL-6 and sIL-6R. Thymocytes from C57BL/6
mice (12-week-old female) were incubated in PBS, 5 mmol/L EDTA, PH7.2, 0.5% BSA, with or without a combination of IL-6 and sIL-6R at 37°C
for 20 minutes, the cells were then stained with RX19 (closed histograms) or control rat myeloma IgG2a (open
histograms).
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Distribution of gp130 on thymocytes and splenic T cells.
gp130 distribution on various T-lymphocyte subpopulations from C57BL/6
mice (12-week-old female) was examined by FACS analysis. As shown in
Fig 3, gp130 was detectable on all
thymocyte subpopulations fractionated in terms of CD4 and CD8
expression, although the expression levels were different among them.
The CD4 /CD8 thymocytes, which are the
most immature subset of T cells in the thymus, displayed the lowest
gp130 expression. As for the gp130 expression level on CD4/CD8 single
positive thymocytes, it was somewhat higher than those on the two other
subpopulations. Among single positive thymocytes, the gp130 expression
level on CD4+/CD8 thymocytes was slightly
lower than that on CD4/CD8+ thymocytes. The
gp130 expression level of CD4+/CD8 or
CD4/CD8+ splenic cells was similar to that
of CD4+/CD8 or
CD4/CD8+ thymocytes, respectively. T cells
from younger (6-week-old) C57BL/6 and (6-week-old) Balb/c mice showed
gp130 expression profiles similar to those of 12-week-old C57BL/6 (data
not shown).
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| Fig 3.
FACS analysis of gp130 on thymocytes and splenic T cells
from C57BL/6 mice. Freshly isolated thymocytes with
CD4/CD8,
CD4+/CD8+,
CD4+/CD8, or
CD4/CD8+ phenotypes and splenic
CD4+ or CD8+ T cells from C57BL/6 mice
(12-week-old female) were analyzed for gp130 expression. Closed and
open histograms show the staining with RX19 and control rat myeloma
IgG2a, respectively.
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Decreased expression of gp130 on splenic T cells of aged
MRL/lpr mice.
MRL/lpr mice carry the mutation of the Fas ligand gene and
develop the lymphoproliferative disease associated with
autoimmunity.18 IL-6 and sIL-6R levels were previously
shown to be elevated in aged MRL/lpr mice.19,20 A
previous report has demonstrated the elevated expression of IL-6R on B
cells and reduced expression on CD4+ T cells in aged
MRL/lpr mice.21 In this investigation, to determine whether the lpr mutation might have some influence on gp130
expression, either directly or indirectly, gp130 levels on T cells from
MRL/lpr were examined. As shown in Fig
4, the expression of gp130 in splenic T
cells is significantly lower in 20-week-old MRL/lpr than in age-matched MRL/n and in 12-week-old C57BL/6 mice (Fig 3). By contrast,
each subpopulation of thymocytes from MRL/lpr displays gp130
expression patterns similar to those of MRL/n and C57BL/6, although the
gp130 level in CD4+/CD8 thymocytes of
MRL/lpr was slightly decreased, as shown in Fig 4B. We further
examined the gp130 expression on Thy1.2+/B220+
T cells known to be abnormally proliferating in aged
MRL/lpr.22 As shown in Fig 4C, T cells of this
phenotype also showed a low level of gp130 expression. To analyze gp130
expression before onset of the disease, T cells of 6-week-old
MRL/lpr were examined. In contrast with aged MRL/lpr,
the gp130 expression levels in both splenic T cells and thymocytes in
younger (6-week-old) MRL/lpr were not reduced (data not shown).
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| Fig 4.
FACS analysis of gp130 on thymocytes and splenic T cells
in aged MRL/lpr and MRL/n. (A) and (C) Cells were prepared from
aged MRL/lpr and MRL/n mice (20-week-old female) spleens.
CD4+, CD8+, and Thy1.2+ cells
were purified by MACS system, and gated by B220 expression. (B) Cells
were prepared from thymus. The cells were then analyzed for gp130
expression. Closed and open histograms show staining with RX19 and
control rat myeloma IgG2a, respectively.
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Reduction of gp130 expression on splenic T cells of IL-6 transgenic
mice and IL-6/IL-6R double transgenic mice.
It is possible that reduced expression of gp130 on MRL/lpr
splenic T cells is caused by overproduction of IL-6 in this strain of
mice. To test this possibility, we further examined gp130 expression in
T cells from transgenic mice overexpressing either IL-6 or IL-6R alone,
or both. As previously reported,23 T cells normally develop
in these transgenic mice. As shown in Fig 5and Table 1, the expression of gp130 on
CD4+ T cells and CD8+ T cells in the spleen was
significantly reduced in transgenic mice overexpressing either IL-6
alone or together with IL-6R. Such reduction was not observed in IL-6R
single transgenic mice. By contrast, gp130 levels on each subpopulation
of thymocytes in these transgenic mice were normal (data not shown) as
was observed in MRL/lpr mice. These results suggest that the
increased IL-6 level may lead to the down-regulation of gp130
expression on peripheral T cells in MRL/lpr, as well as
transgenic mice overexpressing IL-6.
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| Fig 5.
FACS analysis of gp130 on splenic T cells from transgenic
mice. IL-6 single transgenic mice (IL-6+/R
Tg), IL-6R single transgenic mice (IL-6/R+
Tg), IL-6/IL-6R double transgenic mice
(IL-6+/R+ Tg) and wild-type
mice (IL-6/R Tg) were analyzed. Freshly
isolated CD4+ T cells and CD8+ T cells from
spleen were stained with RX19 and control rat myeloma IgG2a. Closed and open histograms show the staining with
RX19 and control rat myeloma IgG2a, respectively.
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Downregulation of gp130 protein on splenic T cells after IL-6
stimulation in vitro.
To further confirm IL-6-mediated downregulation of gp130 on peripheral
T cells, CD4+ or CD8+ splenic T cells from
C57BL/6 mice were cultured with or without IL-6 for 2 days and then
gp130 expression on these cells was analyzed by FACS. As shown in Fig
6, gp130 levels on both CD4+ T
cells and CD8+ T cells that had been cultured with IL-6
were significantly reduced compared with those on T cells cultured
without IL-6. Suppression of gp130 expression on T cells by IL-6 in
vitro was observed in a dose-dependent manner, as shown in Fig
7. These results indicate that IL-6
stimulation can lead to downregulation of the expression of gp130 on
mature T cells in vitro as well as in vivo.
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| Fig 6.
FACS analysis of gp130 on cultured CD4+ and
CD8+ cells. Purified CD4+ and
CD8+ cells from C57BL/6 spleen (12-week-old female) were
cultured in RPMI 1640 medium supplemented with or without IL-6 (10 ng/mL) for 2 days. The cells were then analyzed for gp130 expression. Closed and open histograms show the staining with RX19 and control rat
myeloma IgG2a, respectively.
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| Fig 7.
IL-6 downregulation of gp130 expression on T cells in a
dose-dependent manner. Purified CD4+ and
CD8+ splenic T cells from 6-week-old C57BL/6 mice were
cultured with various concentrations of IL-6 for 2 days. Cells were
washed and stained by RX19 or control rat myeloma IgG2a.
(A) CD4+ T cells. (B) CD8+ T cells.
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DISCUSSION |
In our examination of the distribution of gp130 on splenic T cells and
thymocytes from various mice, we found that although IL-6R was not
detectable by flow cytometry in any thymocyte
subpopulations,24,25 gp130 was readily detectable on all
thymocyte populations, suggesting that immature T cells may use
gp130-stimulatory cytokines other than IL-6. A recent report has shown
that oncostatin M regulates the extrathymic T-cell
development.26 It would be interesting to examine the
expression of a receptor component of the functional oncostatin M
receptor complex, which heterodimerizes with gp130, at various
differentiation stages and in various subpopulations of T cells. Unlike
fresh thymocyte, both CD4+/CD8 and
CD4/CD8+ cells in cultured thymocytes have
been reported to express IL-6R, suggesting that thymocytes may have a
potential to express IL-6R under certain circumstances.21
Therefore, we cannot exclude the possibility that IL-6 can transduce
the signal through gp130 on immature T cells under specific
physiological circumstances.
Our results showed that gp130 was expressed at different levels on
thymocytes of different maturation stages. gp130 was expressed at the
lowest level on the most immature CD4/CD8
thymocytes. Both CD4+/CD8+ and
CD4+/CD8 thymocytes expressed the
intermediate levels of gp130, and the gp130 expression level on
CD4/CD8+ cells was the highest. It has been
reported that the cellular responsiveness to IL-6 varies among the
thymocyte subsets; immature thymocytes are less responsive than mature
subpopulations.27 This finding may be explained by the
difference of gp130 expression among thymocyte subsets.
IL-6 acts on peripheral T cells at an early stage as both a
proliferation factor and a cytotoxic T-cell differentiation
factor.28-31 It has been previously shown that IL-6R is
expressed on peripheral T cells before stimulation in vitro, and the
levels of IL-6R expression on splenic CD4+ T cells and
CD8+ T cells are almost identical.26 By
contrast, gp130 expression on splenic CD8+ T cells was
higher than that on splenic CD4+ T cells, as was observed
in thymocytes. The responsiveness to IL-6 of
CD4+/CD8 has been shown to be lower than
that of CD4/CD8+ T cells.27 This
might reflect the differential gp130 expression levels on these T-cell
subsets.
The MRL/lpr strain is one of the representative animal models
of human autoimmune diseases. The immunologic abnormalities are usually
first observed at the age of around 8 weeks, progressing with
age.32 It has been reported that, in aged MRL/lpr
mice, IL-6R expression is elevated on B cells and absent on peripheral CD4+ cells. Our results showed that gp130 expression on
splenic T cells of aged MRL/lpr decreased significantly. Serum
IL-6 levels in 20-week-old MRL/lpr mice have been reported to
reach up to 0.4 ng/mL.19 Elevated serum sIL-6R levels in
aged MRL/lpr mice have also been shown,20
suggesting that increased levels of IL-6-sIL-6R complex in
MRL/lpr may cause a reduction in gp130 expression on splenic T
cells. In support of this idea, gp130 expression on the splenic
CD4+ cells and CD8+ cells was significantly
decreased both in IL-6 single transgenic mice and in IL-6/IL-6R double
transgenic mice. Serum hIL-6 levels are 0.1 to 5 ng/mL in IL-6
transgenic mice, whereas serum IL-6 levels in wild-type (WT) mice were
only below 0.02 ng/mL.14 In IL-6R single transgenic mice,
the gp130 distribution on splenic T cells was similar to that observed
in WT mice. These results indicated that the expression of gp130 on
splenic T cells was downregulated by continuous gp130 stimulation. This
was confirmed by the in vitro experiment, showing that the gp130
expression on CD4+/CD8 and
CD4/CD8+ splenic T cells was significantly
downregulated by 2 days of incubation with IL-6. In contrast to splenic
T cells, gp130 expression on thymocyte subpopulations was relatively
normal in IL-6 and IL-6/IL-6R transgenics as well as in MRL/lpr
mice. As IL-6R was previously shown to be undetectable on thymocytes of
aged MRL/lpr by flow cytometry,21 it might be
envisaged that failure of gp130 to receive IL-6 signals might explain
the normal gp130 expression on thymocytes of aged MRL/lpr.
However, this was probably not the case because normal gp130 expression
was not affected, even on thymocytes from the transgenic mice
expressing both IL-6 and IL-6R, in which IL-6R was abundantly expressed
on thymocytes. These observations suggest that immature thymocytes may
have a mechanism to regulate gp130 expression differently from that of peripheral T cells.
The precise molecular mechanism of IL-6-dependent downregulation of
gp130 expression is unclear. It was previously shown that administration of IL-6 into mice can upregulate gp130 mRNA in various
tissues, including spleen, kidney, heart, and liver.6 Such
changes of gp130 mRNA were obtained only transiently at 1 to 5 hours
after IL-6 administration in a kinetic study using liver.6
Schoester et al9 also reported that gp130
mRNA is transiently upregulated 4 hours after stimulation by IL-6 in
human monocytes and then reached the basal levels 21 hours later. It appears that regulation of cell-surface expression of gp130 protein is
quite different from that of gp130 mRNA. These observations suggest
that IL-6-dependent downregulation of gp130 expression might take
place at a posttranscriptional level, although gp130 mRNA levels of
lymphocytes freshly isolated from IL-6 transgenic mice and lymphocytes
stimulated by IL-6 in vitro remain to be studied. Dittrich et
al33,34 reported that the cytoplasmic region of gp130 is
required for ligand induced endocytosis and downregulation of the
IL-6R/gp130 complex. Therefore, internalization of the IL-6/IL-6R/gp130
complex may play a role, at least in part, in the IL-6-dependent
downregulation of the gp130 protein observed in the present study.
Cellular responsiveness to cytokines has been considered to be largely
determined by the regulated expression of the ligand-specific receptors, rather than the common signal-transducing chains, such as
gp130. IL-2, IL-4, IL-7, IL-9, and IL-15 use the same chain as an
essential subunit. IL-2R  chain and IL-2R chain are shown to
have restricted expression, whereas the common chain is expressed by monocytes and lymphocytes and is relatively resistant to
regulation.11 The receptor complexes for IL-3, IL-5, and
GM-CSF also contain the common chain.12 Similar to the
common chain, the expression of the common chain is also
relatively resistant to regulation. However, a previous report has
shown that IL-2R chain expression on normal activated T cells was
significantly suppressed by IL-2 stimulation.35
IL-2-induced suppression of IL-2R chain was also demonstrated by
IL-2R promotor-driven luciferase assays.36 Our results
have clearly demonstrated that the expression of the common
signal-transducing chain gp130 in peripheral T cells can be directly
regulated by one of ligands for receptors sharing gp130, IL-6. Cells in
immune and hematopoietic systems often express multiple kinds of
cytokine receptors, which share the same signal transducer; ligands for
such receptors transduce similar intracellular signals through the same
signal transducer, resulting in almost the same biological outcomes.
Under inflammatory conditions, expression of multiple kinds of
cytokines is often induced. Our finding in this study that gp130
expression on T cells is downregulated by IL-6 stimulation suggests
that overexpression of IL-6 may make the target cells desensitized in
response not only to IL-6, but also to the other gp130-stimulating
cytokines. Therefore, the downregulation of gp130 expression by IL-6
may be one example of failsafe mechanisms of the cytokine receptor
systems to avoid hyperstimulation. Although IL-6-induced
downregulation of gp130 expression does not appear to be
so dramatic (10-fold or less) in vivo, downmodulation of physiologic
responses mediated by gp130 is considered significant. This is because
the stimulation of gp130 has been shown to induce expression of
inhibitory proteins that block gp130-mediated intracellular
signals.37-40 Downregulation of gp130 and upregulation of
such inhibitors would cooperatively downmodulate physiologic responses.
To test this hypothesis, it may be necessary to examine the
responsiveness of MRL/lpr and IL-6 transgenic mice to the IL-6
family of cytokines in various circumstances. Such studies are now in
progress.
| |
FOOTNOTES |
Submitted September 29, 1997;
accepted December 16, 1997.
Supported by a Grant-in-Aid from the Ministry of Education Science and
Culture, Japan, and by a grant from the Science and Technology Agency,
Japan. X.J.W. is a fellow of the Osaka Foundation for Promotion of
Clinical Immunology, Japan.
Address reprint requests to Tetsuya Toga, PhD, Department of Molecular
Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10, Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to Drs K. Yoshida, J. Uchida, M. Kamanaka, I. Lee, and
A. Kumanogoh for helpful discussion. We also thank K. Kubota for
excellent technical assistance.
| |
REFERENCES |
1.
Kishimoto T,
Taga T,
Akira S:
Cytokine signal transduction.
Cell
76:253,
1994[Medline]
[Order article via Infotrieve]
2.
Taga T,
Hibi M,
Hirata Y,
Yamasaki K,
Yasukawa K,
Matsuda T,
Hirano T,
Kishimoto T:
Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.
Cell
58:573,
1989[Medline]
[Order article via Infotrieve]
3.
Hibi M,
Murakami M,
Saito M,
Hirano T,
Taga T,
Kishimoto T:
Molecular cloning and expression of an IL-6 signal transducer, gp130.
Cell
63:1149,
1990[Medline]
[Order article via Infotrieve]
4. Taga T, Kishimoto T: Cytokine receptors and signal transduction.
FASEB J 6:3387, 1992
5.
Kishimoto T,
Akira S,
Narazaki M,
Taga T:
Interleukin-6 family of cytokines and gp130.
Blood
86:1243,
1995[Free Full Text]
6.
Saito M,
Yoshida K,
Hibi M,
Taga T,
Kishimoto T:
Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo.
J Immunol
148:4066,
1992[Abstract]
7.
Falus A,
Taga T,
Hibi M,
Murakami M,
Kishimoto T:
Regulation of IL-6 receptor and gp130 expression on human cell lines of lymphoid and myeloid origin.
Cytokine
4:495,
1992[Medline]
[Order article via Infotrieve]
8.
Falus A,
Biro J,
Rakasz E:
Separate regulation of a membrane protein, gp130, present in receptor complex specific for interleukin-6 and other functionally related cytokines.
J Mol Recognit
7:277,
1994[Medline]
[Order article via Infotrieve]
9.
Schoester M,
Heinrich PC,
Graeve L:
Regulation of interleukin-6 receptor expression by interleukin-6 in human monocytes A re-examination.
FEBS Lett
345:131,
1994[Medline]
[Order article via Infotrieve]
10.
Lasfar A,
Wietzerbin J,
Billard C:
Differential regulation of interleukin-6 receptors by interleukin-6 and interferons in multiple myeloma cell lines.
Eur J Immunol
24:124,
1994[Medline]
[Order article via Infotrieve]
11.
Sugamura K,
Asao H,
Kondo M,
Tanaka N,
Ishii N,
Ohbo K,
Nakamura M,
Takeshita T:
The interleukin-2 receptor chain: Its role in the multiple cytokine receptor complexes and T cell development in XSCID.
Annu Rev Immunol
14:179,
1996[Medline]
[Order article via Infotrieve]
12.
Miyajima A,
Kitamura T,
Harada N,
Yokota T,
Arai KI:
Cytokine receptors and signal transduction.
Annu Rev Immunol
10:295,
1992[Medline]
[Order article via Infotrieve]
13.
Suematsu S,
Matsusaka T,
Matsuda T,
Ohno S,
Miyazaki J,
Yamamura K,
Hirano T,
Kishimoto T:
Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice.
Proc Natl Acad Sci USA
89:232,
1992[Abstract/Free Full Text]
14.
Hirota H,
Yoshida K,
Kishimoto T,
Taga T:
Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.
Proc Natl Acad Sci USA
92:4862,
1995[Abstract/Free Full Text]
15.
Karasuyama H,
Melchers F:
Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors.
Eur J Immunol
18:97,
1988[Medline]
[Order article via Infotrieve]
16.
Broudy VC,
Lin NL,
Fox N,
Taga T,
Saito M,
Kaushansky K:
Thrombopoietin stimulates colony-forming unit-megakaryocyte proliferation and megakaryocyte maturation independently of cytokines that signal through the gp130 receptor subunit.
Blood
88:2026,
1995[Abstract/Free Full Text]
17.
Miltenyi S,
Muller W,
Weichel W,
Radbruch A:
High gradient magnetic cell separation with MACS.
Cytometry
11:231,
1990[Medline]
[Order article via Infotrieve]
18.
Wu J,
Zhou T,
Zhang J,
He J,
Gause WC,
Mountz JD:
Correction of accelerated autoimmune disease by early replacement of the mutated lpr gene with the normal Fas apoptosis gene in the T cells of transgenic MRL-lpr/lpr mice.
Proc Natl Acad Sci USA
91:2344,
1994[Abstract/Free Full Text]
19.
Tang B,
Matsuda T,
Akira S,
Nagata N,
Ikehara S,
Hirano T,
Kishimoto T:
Age-associated increase in interleukin 6 in MRL/lpr mice.
Int Immunol
3:273,
1991[Abstract/Free Full Text]
20.
Suzuki H,
Yasukawa K,
Saito T,
Narazaki M,
Hasegawa A,
Taga T,
Kishimoto T:
Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal.
Eur J Immunol
23:1078,
1993[Medline]
[Order article via Infotrieve]
21.
Kobayashi I,
Matsuda T,
Saito T,
Yasukawa K,
Kikutani H,
Hirano T,
Taga T,
Kishimoto T:
Abnormal distribution of IL-6 receptor in aged MRL/lpr mice: Elevated expression on B cells and absence on CD4+ cells.
Int Immunol
4:1407,
1992[Abstract/Free Full Text]
22.
Asano T,
Tomooka S,
Serushago BA,
Himeno K,
Nomoto K:
A new subset expression B220 and CD4 in lpr mice: Defects in the response to mitogens and in the production of IL-2.
Clin Exp Immunol
74:36,
1988[Medline]
[Order article via Infotrieve]
23.
Peters M,
Schirmacher P,
Goldschmitt J,
Oderthal M,
Peschel C,
Fattori E,
Ciliberto G,
Dienes HP,
Meyer Zum Buschenfelde KH,
Rose John S:
Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice.
J Exp Med
185:755,
1997[Abstract/Free Full Text]
24.
Taga T,
Kawanishi Y,
Hardy RR,
Hirano T,
Kishimoto T:
Receptors for B cell stimulatory factor 2: Quantitation, specificity, distribution, and regulation of their expression.
J Exp Med
166:967,
1987[Abstract/Free Full Text]
25.
Hirata Y,
Taga T,
Hibi M,
Nakano N,
Hirano T,
Kishimoto T:
Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies.
J Immunol
143:2900,
1989[Abstract]
26.
Clegg CH,
Rulffes JT,
Wallace PM,
Haugen HS:
Regulation of an extrathymic T-cell development pathway by oncostatin M.
Nature
384:261,
1996[Medline]
[Order article via Infotrieve]
27.
Uyttenhove C,
Coulie PG,
Van Snick J:
T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor.
J Exp Med
167:1417,
1988[Abstract/Free Full Text]
28.
Hirano T,
Taga T,
Nakano N,
Yasukawa K,
Kashiwamura S,
Shimizu K,
Nakajima K,
Pyun KH,
Kishimoto T:
Purification to homogeneity and characterization of human B cell differentiation factor (BCDF or BSFp-2).
Proc Natl Acad Sci USA
82:5490,
1985[Abstract/Free Full Text]
29.
Takai Y,
Wong GG,
Clark SC,
Burakoff SJ,
Herrmann SH:
B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes.
J Immunol
140:508,
1988[Abstract]
30.
Okada M,
Kitahara M,
Kishimoto S,
Matsuda T,
Hirano T,
Kishimoto T:
IL-6/BSF-2 functions as a killer factor in the in vitro induction of cytotoxic T cells.
J Immunol
141:1543,
1988[Abstract]
31.
Lotz M,
Jirik F,
Kabouridis P,
Tsoukas C,
Hirano T,
Kishimoto T,
Carson DA:
B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes.
J Exp Med
167:1253,
1988[Abstract/Free Full Text]
32.
Hoffman RW,
Alspaugh MA,
Waggie KS,
Durham JB,
Walker SE:
Sjögren's syndrome in MRL/l and MRL/n mice.
Arthritis Rheum
27:157,
1984[Medline]
[Order article via Infotrieve]
33.
Dittrich E,
Rose-John S,
Gerhartz C,
Mullberg J,
Stoyan T,
Yasukawa K,
Heinrich PC,
Graeve L:
Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand-induced endocytosis of the IL-6 receptor.
J Biol Chem
269:19014,
1994[Abstract/Free Full Text]
34.
Dittrich E,
Haft CR,
Muys L,
Heinrich PC,
Graeve L:
A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor.
J Biol Chem
271:5487,
1996[Abstract/Free Full Text]
35.
Kondo M,
Ohashi Y,
Tada K,
Nakamura M,
Sugamura K:
Expression of the mouse interleukin-2 receptor chain in various cell populations of the thymus and spleen.
Eur J Immunol
24:2026,
1994[Medline]
[Order article via Infotrieve]
36.
Ohbo K,
Takasawa N,
Ishii N,
Tanaka N,
Nakamura M,
Sugimura K:
Functional analysis of the human interleukin-2 receptor chain gene promoter.
J Biol Chem
270:7479,
1995[Abstract/Free Full Text]
37.
Starr R,
Willson TA,
Viney EM,
Murray LJL,
Rayner JR,
Jenkins BJ,
Gonda TJ,
Alexander WS,
Metcalf D,
Nicola NA,
Hilton DJ:
A family of cytokine-inducible inhibitors of signalling.
Nature
387:917,
1997[Medline]
[Order article via Infotrieve]
38.
Endo TA,
Masuhara M,
Yokouchi M,
Suzuki R,
Sakamoto H,
Mitsui K,
Matsumoto A,
Tanimura S,
Ohtsubo M,
Misawa H,
Miyazaki T,
Leonor N,
Taniguchi T,
Fujita T,
Kanakura Y,
Komiya S,
Yoshimura A:
A new protein containing an SH2 domain that inhibits JAK kinases.
Nature
387:921,
1997[Medline]
[Order article via Infotrieve]
39.
Naka T,
Narazaki M,
Hirata M,
Matsumoto T,
Minamoto S,
Aono A,
Nishimoto N,
Kajita T,
Taga T,
Yoshizaki K,
Akira S,
Kishimoto T:
Structure and function of a new STAT-induced STAT inhibitor.
Nature
387:924,
1997[Medline]
[Order article via Infotrieve]
40.
Minamoto T,
Ikegame K,
Ueno K,
Narazaki M,
Naka T,
Yamamoto H,
Matsumoto T,
Saito H,
Hosoe S,
Kishimoto T:
Cloning and functional analysis of new members of STAT inhibitor (SSI) family: SSI-2 and SSI-3.
Biochem Biophys Res Commun
237:79,
1997[Medline]
[Order article via Infotrieve]
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Abstract
Introduction
Abstract