Intranasal Administration of Interleukin-27 Alleviates Airway Allergic Inflammation of Ovalbumin-induced Mouse Asthma Model <i>via</i> STAT1 Signal Pathway_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

SuXiaoqiong ¹ ^Δ , PanJue ¹ ^Δ , JinJianjun ² , XuKan ³ , DengZhi ⁴ ,  ChenZhihong ¹

1. Department of Respiratory Medicine, Zhongshan Hospital Fudan University, Shanghai, 200032, China;
2. ;
3. ;
4. ;

Corresponding author：

ChenZhihong, Email: czh60@hotmail.com

Keywords：

Interleukin-27; Th2 differentiation; Signal transducer and activator of transcription-1

DOI：

10.7507/1671-6205.2015110

Video：

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Objective To observe whether interleukin-27 (IL-27) intervention could diminish allergic airway inflammation of mouse asthma induced by ovalbumin (OVA) and to investigate the related molecular mechanisms. Methods Sixty female C57/6J mice were randomly divided into six groups, a control group, an asthma group, two IL-27 prevention groups and two IL-27 treatment groups. Based on being sensitized and challenged with OVA in the asthma model, two kinds of IL-27 intervention asthma models were set up, one of which was low-dose multiple prevention model, the other was high-dose few times treatment model. HE stain and inflammation score were done for the lungs. CD4⁺ T cells were purified from mice spleen and cultured under Th2 medium with/without IL-27. Interleukin-4 (IL-4) was measured by ELISA. CD4⁺ T cells were cultured under different stringent Th2 medium and stimulated by IL-27. The level of total signal transducer and activator of transcription-1 (STAT1) protein and phos-STAT1 were tested by Western blot. Results In low-dose multiple prevention group, IL-27 inhibited inflammation around bronchial and vascular obviously, the inflammation score was lower than the asthma group (P < 0.05), while the treatment group had no obvious statistical significance (P > 0.05). IL-27 repressed Th2 differentiation of naïve CD4⁺ T cells which was independent of interferon-γand IL-10. This effect was via STAT1 signaling pathway. CD4⁺ T cells from asthma mice or cultured under high-IL-4 inducing medium were found impairment of STAT1 phosphorylation. Conclusions IL-27 could inhibit Th2 differentiation of naïve CD4⁺ T cells, but not in already committed Th2-CD4⁺ T cells. The inhibition effect of IL-27 for airway inflammation is obvious in prevention group, while the treatment group shows obviously resistance to inhibitory effect of IL-27. Already committed Th2-CD4⁺ T cells existed in asthma airway might be the reason for IL-27 resistance.

Citation： SuXiaoqiong, PanJue, JinJianjun, XuKan, DengZhi, ChenZhihong. Intranasal Administration of Interleukin-27 Alleviates Airway Allergic Inflammation of Ovalbumin-induced Mouse Asthma Model via STAT1 Signal Pathway. Chinese Journal of Respiratory and Critical Care Medicine, 2015, 14(5): 442-448. doi: 10.7507/1671-6205.2015110 Copy

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5.	Usui T, Preiss JC, Kanno Y, et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med, 2006, 203:755-766.
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7.	Hida SM, Tadachi TS, Taki S. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood, 2005, 106:2011-2017.
8.	Miyazaki Y, Inoue H, Matsumura M, et al. Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J Immunol, 2005, 175:2401-2407.
9.	Artis D, Villarino A, Silverman M, et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J Immunol, 2004, 173:5626-5634.
10.	Yoshimoto T, Yasuda K, Mizuguchi J, et al. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells:a novel therapeutic way for Th2-mediated allergic inflammation. J Immunol, 2007, 179:4415-4423.
11.	El-behi M, Ciric B, Yu S, et al. Differential effect of IL-27 on developing versus committed Th17 Cells. J Immunol, 2009, 183:4957-4967.
12.	Chen ZH, Wang SZ, Erekosima N, et al. IL-4 confers resistance to IL-27 mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling. J Allergy Clin Immunol, 2013, 132:912-921.
13.	Curtis JL, Byrd PK, Warnock ML, et al. Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen. J Clin Invest, 1991, 88:1244-1254.
14.	Leung DY, Gao PS, Grigoryev DN, et al. Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-gamma response. J Allergy Clin Immunol, 2011, 127:965-973.
15.	Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol, 2008, 19:414-422.
16.	O'Shea JJ, Gadina M, Kanno Y. Cytokine signaling:birth of a pathway. J Immunol, 2011, 187:5475-5478.
17.	Dupuis S, Jouanguy E, Al-Hajjar S, et al. Impaired response to interferon-alpha/beta and lethal viral isease in human STAT1 deficiency. Nat Genet, 2003, 33:388-391.
18.	Dulek DE, Peebles RS Jr. Viruses and asthma. Biochim Biophys Acta, 2011, 1810:1080-1090.
19.	孔存权, 连利霞, 彭霞, 等.过敏性哮喘小鼠树突状细胞负荷Der p2抗原后表面标志物表达与细胞因子分泌水平的研究.中国呼吸与危重监护杂志, 2014, 13:398-401.
20.	崔学超, 王刚.针刺治疗支气管哮喘研究进展.中国呼吸与危重监护杂志, 2013, 12:416-422.
21.	田佳, 万毅新, 王晓平.甲壳质酶蛋白在支气管哮喘患者血清中的表达及意义.中国呼吸与危重监护杂志, 2014, 13:116-119.
22.	Yoshida H, Nakaya M, Miyazaki Y. Interleukin 27:a double-edged sword for offense and defense. J Leukoc Biol, 2009, 86:1295-1303.

1. Huang H. Suppressing allergic immune responses. Front Biosci (Elite Ed), 2011, 3:864-870.
2. Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science, 2002, 295:338-342.
3. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 2000, 100:655-669.
4. Zhu J, Jankovic D, Oler AJ, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity, 2012, 37:660-673.
5. Usui T, Preiss JC, Kanno Y, et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med, 2006, 203:755-766.
6. Finotto S, Neurath MF, Glickman JN, et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science, 2002, 295:336-338.
7. Hida SM, Tadachi TS, Taki S. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood, 2005, 106:2011-2017.
8. Miyazaki Y, Inoue H, Matsumura M, et al. Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J Immunol, 2005, 175:2401-2407.
9. Artis D, Villarino A, Silverman M, et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J Immunol, 2004, 173:5626-5634.
10. Yoshimoto T, Yasuda K, Mizuguchi J, et al. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells:a novel therapeutic way for Th2-mediated allergic inflammation. J Immunol, 2007, 179:4415-4423.
11. El-behi M, Ciric B, Yu S, et al. Differential effect of IL-27 on developing versus committed Th17 Cells. J Immunol, 2009, 183:4957-4967.
12. Chen ZH, Wang SZ, Erekosima N, et al. IL-4 confers resistance to IL-27 mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling. J Allergy Clin Immunol, 2013, 132:912-921.
13. Curtis JL, Byrd PK, Warnock ML, et al. Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen. J Clin Invest, 1991, 88:1244-1254.
14. Leung DY, Gao PS, Grigoryev DN, et al. Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-gamma response. J Allergy Clin Immunol, 2011, 127:965-973.
15. Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol, 2008, 19:414-422.
16. O'Shea JJ, Gadina M, Kanno Y. Cytokine signaling:birth of a pathway. J Immunol, 2011, 187:5475-5478.
17. Dupuis S, Jouanguy E, Al-Hajjar S, et al. Impaired response to interferon-alpha/beta and lethal viral isease in human STAT1 deficiency. Nat Genet, 2003, 33:388-391.
18. Dulek DE, Peebles RS Jr. Viruses and asthma. Biochim Biophys Acta, 2011, 1810:1080-1090.
19. 孔存权, 连利霞, 彭霞, 等.过敏性哮喘小鼠树突状细胞负荷Der p2抗原后表面标志物表达与细胞因子分泌水平的研究.中国呼吸与危重监护杂志, 2014, 13:398-401.
20. 崔学超, 王刚.针刺治疗支气管哮喘研究进展.中国呼吸与危重监护杂志, 2013, 12:416-422.
21. 田佳, 万毅新, 王晓平.甲壳质酶蛋白在支气管哮喘患者血清中的表达及意义.中国呼吸与危重监护杂志, 2014, 13:116-119.
22. Yoshida H, Nakaya M, Miyazaki Y. Interleukin 27:a double-edged sword for offense and defense. J Leukoc Biol, 2009, 86:1295-1303.

Chinese Journal of Respiratory and Critical Care Medicine

Intranasal Administration of Interleukin-27 Alleviates Airway Allergic Inflammation of Ovalbumin-induced Mouse Asthma Model via STAT1 Signal Pathway

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