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Triptolide

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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