Regulative Effects of Th9 Cell Relative Factors in Pulmonary Fibrosis in Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

 BaoWenhua , WangJin , LiShumin , YangXiaodong , MaXuemei

Department of Respiratory Medicine, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, 154000, China;

Corresponding author：

BaoWenhua, Email: baowenhua3@sina.com

Keywords：

Pulmonary fibrosis; Th9; Transcription factor; PU.1; Interferon regulatory factor 4

DOI：

10.7507/1671-6205.2016054

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To observe the effects of Th9 cell relative factors, including PU.1, interferon regulatory factor 4 (IRF4) and interleukin 4 (IL-4), in rats with pulmonary fibrosis. Methods Ninety SD rats were randomly divided into 3 groups, ie. a normal group, a pulmonary fibrosis group, and a dexamethasone treatment group, with 30 rats in each group. Ten rats in each group were sacrificed respectively on 7^th, 14^th, 28^th days. Model rats were induced by injecting bleomycin into trachea. Real-time PCR was applied to detect mRNA expression of PU.1 and IRF4 in bronchoalveolar lavage fluid. IL-4 in the peripheral blood was measured by ELISA. Results In the normal group, the lung tissue was normal without inflammatory reaction and fibrosis at any time points. In the pulmonary fibrosis group, at the early stage the lung tissue showed alveolar inflammation with a large number of macrophages and other inflammatory cells infiltratation in the pulmonary interstitial and alveolar cavity; on 14^th day, part of the alveolar structure disappeared, inflammatory cells infiltrated slightly, while the alveolar septum was mildly widened and fibroblasts proliferated; on 28^th day, alveolar structure was destructed, partial alveolar walls were collapsed, alveolar septuml was significantly widened, extracellular matrix was hyperplastic, a wide range of fibrosis occured. In the dexamethasone treatment group, the alveolar structure exsisted completely, and the inflammatory cell infiltration, widened alveolar septum and fibrosis were significantly lighter than those in the pulmonary fibrosis group. PU.1 mRNA was significantly lower in the pulmonary fibrosis group compared with the normal group. Compared with the pulmonary fibrosis group, PU.1 mRNA were lower on 14^th day and 28^th day in the dexamethasone treatment group (P < 0.05). PU.1 mRNA increased from 7^th day, reached peak on 14^th day, and declined on 28^th day. IRF4 mRNA was significantly lower in the pulmonary fibrosis group compared with the normal group. Compared with the pulmonary fibrosis group, IRF4 mRNA was lower on 28^th day in the dexamethasone treatment group (P < 0.05). There was a positive correlation between the content of IRF4 mRNA and IL-4 on 14^th day in the pulmonary fibrosis group (r=0.044, P < 0.05). Conclusion PU.1 and IRF4 play a role in inflammation leading to pulmonary interstitial fibrosis, and IL-4 may regulate Th9 cells through activating IRF4.

Citation： Bao Wenhua, Wang Jin, Li Shumin, Yang Xiaodong, Ma Xuemei. Regulative Effects of Th9 Cell Relative Factors in Pulmonary Fibrosis in Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2016, 15(3): 227-231. doi: 10.7507/1671-6205.2016054 Copy

1.	Huaux F, Liu T, McGarry B, et al. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J Immunol, 2003, 171:5470-5481.
2.	Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev, 2013, 252:104-115.
3.	Syrbu S, Thrall RS, Smilowitz HM. Sequential appearance of inflammatory mediators in rat bronchoalveolar lavage fluid after oleic acid-induced lung injury. Exp Lung Res, 1996, 22:33-49.
4.	Rothenberg EV, Moore JE, Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol, 2008, 8:9-21.
5.	Veldhoen M, Uyttenhove C, van Snick J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol, 2008, 9:1341-1346.
6.	Tamura T, Ysnsi H, Savitsky D, et al. The IRF family transcription factors in immumity and oncogenesis. Annu Rev Immunol, 2008, 26:535-584.
7.	Shaffer AL, Emre NC, Romesser PB, et al. IRF4: immunity. Malignancy! Therapy? Clin Cancer Res, 2009, 15:2954-2961.
8.	Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol, 2015, 15:295-307.
9.	Hoppenot D, Malakauskas K, Lavinskiene S, et al. Peripheral blood Th9 cells and eosinophil apoptosis in asthma patients. Medicina (Kaunas), 2015, 51:10-17.
10.	Jones CP, Gregory LG, Causton B, et al. Activin A and TGF-β promote T(H)9 cell-mediated pulmonary allergic pathology. J Allergy Clin Immunol, 2012, 129:1000-1010.
11.	Gauldie J, Bonniaud P, Sime P, et al. TGF-beta, Smad3 and the process of progressive fibrosis. Biochem Soc Trans, 2007, 35:661-664.
12.	Goswami R, Kaplan MH. Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol, 2012, 189:3026-3033.
13.	Staudt V, Bothur E, Klein M, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity, 2010, 33:192-202.
14.	Li HP, Li X, He GJ, et al. The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin-induced pulmonary fibrosis in rats.Respirology, 2004, 9:25-32.
15.	Chen F, Gong L, Zhang L, et al. Short courses of low dose dexamethasone delay bleomycin-induced lung fibrosis in rats.Eur J Pharmacol, 2006, 536:287-295.
16.	Goswami R, Jabeen R, Yagi R, et al. STAT6-dependent regulation of Th9 development. J Immunol, 2012, 188:968-975.
17.	Jabeen R, Kulkarni A, Nguyen ET, et al. Th9 cell development requires a BATF-regulated transcriptional network. J Clin Invest, 2013, 123:4641-4653.

1. Huaux F, Liu T, McGarry B, et al. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J Immunol, 2003, 171:5470-5481.
2. Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev, 2013, 252:104-115.
3. Syrbu S, Thrall RS, Smilowitz HM. Sequential appearance of inflammatory mediators in rat bronchoalveolar lavage fluid after oleic acid-induced lung injury. Exp Lung Res, 1996, 22:33-49.
4. Rothenberg EV, Moore JE, Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol, 2008, 8:9-21.
5. Veldhoen M, Uyttenhove C, van Snick J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol, 2008, 9:1341-1346.
6. Tamura T, Ysnsi H, Savitsky D, et al. The IRF family transcription factors in immumity and oncogenesis. Annu Rev Immunol, 2008, 26:535-584.
7. Shaffer AL, Emre NC, Romesser PB, et al. IRF4: immunity. Malignancy! Therapy? Clin Cancer Res, 2009, 15:2954-2961.
8. Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol, 2015, 15:295-307.
9. Hoppenot D, Malakauskas K, Lavinskiene S, et al. Peripheral blood Th9 cells and eosinophil apoptosis in asthma patients. Medicina (Kaunas), 2015, 51:10-17.
10. Jones CP, Gregory LG, Causton B, et al. Activin A and TGF-β promote T(H)9 cell-mediated pulmonary allergic pathology. J Allergy Clin Immunol, 2012, 129:1000-1010.
11. Gauldie J, Bonniaud P, Sime P, et al. TGF-beta, Smad3 and the process of progressive fibrosis. Biochem Soc Trans, 2007, 35:661-664.
12. Goswami R, Kaplan MH. Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol, 2012, 189:3026-3033.
13. Staudt V, Bothur E, Klein M, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity, 2010, 33:192-202.
14. Li HP, Li X, He GJ, et al. The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin-induced pulmonary fibrosis in rats.Respirology, 2004, 9:25-32.
15. Chen F, Gong L, Zhang L, et al. Short courses of low dose dexamethasone delay bleomycin-induced lung fibrosis in rats.Eur J Pharmacol, 2006, 536:287-295.
16. Goswami R, Jabeen R, Yagi R, et al. STAT6-dependent regulation of Th9 development. J Immunol, 2012, 188:968-975.
17. Jabeen R, Kulkarni A, Nguyen ET, et al. Th9 cell development requires a BATF-regulated transcriptional network. J Clin Invest, 2013, 123:4641-4653.

Chinese Journal of Respiratory and Critical Care Medicine

Regulative Effects of Th9 Cell Relative Factors in Pulmonary Fibrosis in Rats

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