Inhibits
the
Differentiation
of
Th17
cells
and
Suppresses
Collagen-induced
Arthritis
Y.
Wang,
L.
Jia
&
C.-y.
Wu
Introduction
Traditionally,
CD4
+
T
cells
have
been
divided
into
T
helper
type
1
(Th1)
and
Th2
subsets
based
on
their
spe-
cific
cytokine
profiles
and
biological
functions
[
1
]
.
Recent
studies
have
demonstrated
that
interleukin-17
(IL-17)-
producing
T
cells
named
Th17
cells
constitute
a
separate
T-cell
subset
[
2,
3
]
.
Th17
cells
have
been
demonstrated
to
play
an
important
role
in
mediating
immunity
and
autoimmune
diseases.
Th17
cells,
a
third
independent
T-helper
cell
subset,
require
specific
cytokines
and
transcription
factors
for
their
differentiation.
IL-6
and
transforming
growth
fac-
tor-
b
(TGF-
b
)
are
recognized
as
crucial
factors
necessary
for
the
differentiation
of
mouse
naı
¨
ve
T
cells
into
Th17
cells
[
4,
5
]
.
A
recent
study
demonstrates
that
retroviral
transduction
of
a
constitutively
active
STAT3
into
differentiating
T
cell
cultures
enhances
IL-17
production
[
6
]
.
Moreover,
STAT3
deficiency
in
CD4
+
T
cells
results
in
impaired
Th17
development
[
7
]
.
Therefore,
it
is
believed
that
STAT3,
activated
by
IL-6,
is
a
key
signal-
ling
molecule
involved
in
Th17
differentiation.
Autoimmune
diseases,
such
as
rheumatoid
arthritis
(RA),
have
been
previously
thought
to
be
mediated
by
Th1
cells
[
8
]
.
However,
anti-IFN-
c
-treated
mice,
IFN-
c
-
or
IFN-
c
R-deficient
mice
indeed
develop
collagen-
induced
arthritis
(CIA)
[
9,
10
]
.
Recent
studies
have
revealed
that
treatment
with
a
neutralizing
anti–IL-17
antibody
after
the
onset
of
CIA
significantly
reduces
the
severity
of
CIA
[
11
]
.
And
IL-17-deficient
mice
are
resis-
tant
to
the
development
of
CIA
[
12
]
.
Moreover,
high
level
of
IL-17
expression
is
detected
in
the
target
tissues
during
the
progression
of
various
human
autoimmune
diseases
[
13
]
.
These
data
suggest
that
Th17
cells
but
not
Department
of
Immunology,
Zhongshan
School
of
Medicine,
State
Ministry
of
Education
Key
Laboratory
of
Tropical
Diseases
Control
Research,
Sun
Yat-sen
University,
Guangzhou,
Guangdong,
China
Received
6
May
2008;
Accepted
in
revised
form
8
June
2008
Correspondence
to
:
Dr
C.-y.
Wu,
Department
of
Immunology,
Zhongshan
School
of
Medicine,
Sun
Yat-sen
University,
74
Zhongshan
2nd
Road,
Guangzhou,
Guangdong
Province
510080,
China.
E-mail:
changyou_wu@yahoo.com
Abstract
Triptolide,
a
diterpenoid
isolated
from
the
Chinese
herb
Tripterygium
wilfordii
Hook
F,
has
been
demonstrated
to
be
effective
in
the
treatment
of
a
variety
of
autoimmune
diseases.
T
helper
type
17
(Th17)
cells
represent
a
novel
subset
of
CD4
+
T
cells
involved
in
the
immunopathogenesis
of
autoimmune
diseases.
Currently,
the
effects
of
triptolide
on
the
differentiation
of
Th17
cells
remain
unclear.
Here,
we
found
that
triptolide
significantly
inhibited
the
generation
of
Th17
cells
from
murine
splenocytes
and
purified
CD4
+
T
cells
in
a
dose-
dependent
manner.
The
suppressive
effects
of
triptolide
were
persistent
even
after
it
had
been
removed
from
cell
cultures.
Importantly,
triptolide
inhibited
the
transcription
of
interleukin-17
(IL-17)
mRNA
and
IL-6-induced
phosphor-
ylation
of
STAT3,
a
key
signalling
molecule
involved
in
the
development
of
Th17
cells.
Moreover,
these
suppressive
effects
of
triptolide
on
Th17
differen-
tiation
were
not
due
to
cytotoxicity
of
triptolide
because
the
numbers
of
viable
cells
had
no
significant
difference
between
triptolide-treated
and
non-
triptolide-treated
cells.
In
vivo
studies
demonstrated
that
the
treatment
of
collagen-induced
arthritis
(CIA)
mice
with
triptolide
reduced
arthritis
scores
and
swollen
degree
of
joints.
At
the
same
time,
the
levels
of
collagen
type
II
(CII)-specific
IL-17
production
and
the
percentages
of
CII-specific
IL-17
+
CD4
+
T
cells
in
the
cells
from
draining
lymph
nodes
and
spleens
were
significantly
reduced
in
CIA
mice
treated
with
triptolide.
These
results
suggested
that
tri-
ptolide
displayed
an
immunosuppressive
effect
on
CIA
by
down-regulating
CII-specific
Th17
cells.
Taken
together,
our
results
may
provide
a
new
light
on
the
potential
mechanism
of
the
immunosuppressive
and
anti-inflammatory
effects
of
triptolid.
B
A
S
I
C
I
M
M
U
N
O
L
O
G
Y
doi:
10.1111/j.1365-3083.2008.02147.x
..................................................................................................................................................................
Ó
2008
The
Authors
Journal
compilation
Ó
2008
Blackwell
Publishing
Ltd.
Scandinavian
Journal
of
Immunology
68,
383–390
383
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