IL-27 attenuates airway inflammation in a mouse asthma model via the STAT1 and GADD45γ/p38 MAPK pathways.
BACKGROUND
Asthma is prone to Th2-mediated chronic airway inflammation. Interleukin-27 (IL-27) is a member of the IL-12 family that promotes the differentiation of Th1 cells and inhibits Th2 cells. We use human/mouse CD4+T cells to see whether IL-27 could inhibit IL-4 production in vitro and then observe whether IL-27 administration could alleviate allergic airway inflammation in vivo by mice asthma model.


METHODS
We isolated and cultured CD4+T cells from healthy humans and mice to test whether IL-27 could inhibit IL-4 production under different conditions. In vivo study, the effect of IL-27 was examined using two types of intra-nasal (i.n.) administration: low-dose-multiple-times prevention or high-dose-limited-times treatment in murine asthma models. The expression levels of signal transducer and activator of transcription-1 (STAT1) and growth arrest and DNA damage 45-γ (GADD45γ)/p38 mitogen activated protein kinase (p38 MAPK) in lung tissues were measured using qPCR and Western blotting.


RESULTS
In vitro, although IL-27 could inhibit naïve CD4+T cell differentiate into Th2 cells, but it could not redifferentiate already committed Th2 cells. In vivo, preventative administration of IL-27 attenuated allergic inflammation and airway hyperreactivity, whereas treatment group had no significant effect. In the asthma group, the phosphorylation of STAT1 was impaired, while GADD45γ and p38 MAPK exhibited no obvious changes. Preventative administration of IL-27 could either reverse the impairment of STAT1 or strengthen the expression of GADD45γ and p38 MAPK, whereas treatment group had no significant effect.


CONCLUSIONS
Preventative administration of IL-27 improved the pathological changes in mouse asthma models via both the STAT1 and GADD45γ/p38 MAPK pathways while therapeutic administration of IL-27 had no significant effect, which may be due to the presence of already differentiated Th2 cells in asthmatic airways that resist IL-27 inhibition.
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China.|Department of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
Xiaoqiong
X
Su
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China.
Jue
J
Pan
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China.
Fengxi
F
Bai
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China.
Honglei
H
Yuan
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China.
Nian
N
Dong
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China.
Dandan
D
Li
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China. xiangdong.wang@clintransmed.org.|Research Center of Zhongshan Hospital, Fudan University, No 180 Fenglin Road, Shanghai, 200032, China. xiangdong.wang@clintransmed.org.|Department of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. xiangdong.wang@clintransmed.org.
Xiangdong
X
Wang
Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No.180 Fenglin Road, Shanghai, China. czh60@hotmail.com.
Zhihong
Z
Chen
GADD45γ; IL-27; STAT1; Th2 development; p38 MAPK
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