Effect of 1,25-(OH)<sub>2</sub>D<sub>3</sub> on JNK/AP-1 and glucocorticoid receptor of T lymphocytes in steroid-resistant asthmatics _Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YANG Haihua ¹ , LONG Feng ¹ , LI Shengqing ² , ZHANG Xia ¹ ,  JIN Xianqiao ²

1. Department of Respiratory Medicine, Huashan Hospital North, Fudan University, Shanghai, 201907, P.R.China;
2. Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P.R.China;

Corresponding author：

JIN Xianqiao, Email: jinxianqiao@126.com

Keywords：

Vitamin D; Steroid resistant asthmatics; T lymphocyte; JNK; AP-1; Glucocorticoid receptor

DOI：

10.7507/1671-6205.201610033

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Objective To observe the level of vitamin D in patients with steroid resistant (SR) asthma, and investigate the effect of 1,25-(OH)₂D₃ on JNK/AP-1 and glucocorticoid receptor of T lymphocytes in SR asthmatics. Methods Sixty-two outpatients and inpatients with asthma with acute exacerbation between 2014 and 2015 were recruited in the study, including 26 cases of steroid sensitive (SS) asthmatics and 36 cases of SR asthmatics. Meanwhile 25 healthy volunteers were recruited as control. Clinical data were collected and peripheral venous blood was sampled for measuring the level of 25-(OH)D and separating the T lymphocytes. T lymphocytes were assigned to six groups, ie. a healthy control group (Group A), a SS asthmatics control group (Group B), a SR asthmatics control group (Group C), a SR asthmatics with JNK inhibitor (SP600125)+1,25-(OH)₂D₃ group (Group D), a SR asthmatics with JNK inhibitor (SP600125) group (Group E), and a SR asthmatics with 1,25-(OH)₂D₃ group (Group F). T lymphocytes were cultured for 48 hours. By the end of culture, the expression of phospho-JNK (p-JNK) and phospho-glucocorticoid receptor (p-GR) of T lymphocytes were detected by Western blot method, and the expression of c-Jun mRNA was detected by RT-PCR method. Results The level of 25-(OH) D was lower in Group B and Group C than Group A (P<0.05), and lower in Group C than Group B (P<0.05). The level of p-JNK was higher in Group B and Group C than Group A (P<0.05), higher in Group C than Group B (P<0.05), lower in Group E and Group F than Group C (P<0.05), lower in Group D than Group F (P<0.05). The level of p-GR was lower in Group C than Group A and Group B (P<0.05), higher in Group E and Group F than Group C (P<0.05), higher in Group D than Group F (P<0.05). The level of c-Jun mRNA was higher in Group B and Group C than Group A (P<0.05), higher in Group C than Group B (P<0.05), lower in Group E and Group F than Group C (P<0.05), and lower in Group D than Group F (P<0.05). The 25-(OH) D level was negatively correlated with the expression of p-JNK and c-Jun mRNA in Group C (r=–0.69, r=–0.65, P<0.05). However, there was a positive correlation between the 25-(OH) D level and p-GR (r=0.72, P<0.05). Conclusions There is a high prevalence of vitamin D deficiency or lack in SR asthmatics. 1,25-(OH)₂D₃ can promote the expression of p-GR by inhibiting the JNK/AP-1 signaling pathway of T lymphocytes in SR asthmatics, which may be one of the mechanisms of vitamin D to improve glucocorticoid resistance in SR asthmatics.

Citation： YANG Haihua, LONG Feng, LI Shengqing, ZHANG Xia, JIN Xianqiao. Effect of 1,25-(OH)₂D₃ on JNK/AP-1 and glucocorticoid receptor of T lymphocytes in steroid-resistant asthmatics . Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(2): 155-159. doi: 10.7507/1671-6205.201610033 Copy

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2.	Kim RY, Rae B, Neal R, et al. Elucidating novel disease mechanisms in severe asthma. Clin Transl Immunol, 2016, 5(7): e91.
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11.	刘瑶琦, 赵海金, 蔡绍曦. 补充维生素 D: 哮喘治疗新手段. 中国呼吸与危重监护杂志, 2016, 15(3): 305-309.
12.	宋颖芳, 洪景芳, 柳德灵,等. 1,25-二羟维生素 D3 对慢性哮喘小鼠气道重塑中 MMP-9 及 NF-κB 表达的影响. 中国呼吸与危重监护杂志, 2013, 12(1): 36-40.
13.	郝敏, 林江涛. 糖皮质激素抵抗性支气管哮喘诊治进展. 中华结核和呼吸杂志, 2014, 37(4): 296-298.
14.	孙永昌,罗慰慈. 激素抵抗型哮喘发生机制的研究. 国外医学呼吸系统分册, 1995, 15（2）: 58-60.
15.	Karras SN, Shah I, Petroczi A, et al. An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: implications of a new assay on the roles of vitamin D forms. Nutr J, 2013, 12: 77.
16.	Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med, 2011, 364(3): 248-254.
17.	Yao TC, Tu YL, Chang SW, et al. Serum 25-hydroxyvitamin D levels in relation to lung function and exhaled nitric oxide in children. J Pediatr, 2014, 165(6): 1098-1103. e1.
18.	Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA, 2014, 311(20): 2083-2091.
19.	Malinovschi A, Masoero M, Bellocchia M, et al. Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients. Respir Res, 2014, 15: 131.
20.	Bantel H, Schmitz ML, Raible A, et al. Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsiveness. FASEB J, 2002, 16(13): 1832-1834.
21.	Miraglia Del Giudice M, Allegorico A. The role of vitamin D in allergic diseases in children. J Clin Gastroenterol, 2016, 50 Suppl 2: S133-S135.

1. Trevor JL, Deshane JS. Refractory asthma: mechanisms, targets, and therapy. Allergy, 2014, 69(7): 817-827.
2. Kim RY, Rae B, Neal R, et al. Elucidating novel disease mechanisms in severe asthma. Clin Transl Immunol, 2016, 5(7): e91.
3. Abe A, Ohtomo T, Koyama S, et al. Comparative analysis of steroid sensitivity of T helper cells in vitro and in vivo. Int Arch Allergy Immunol, 2011, 155 Suppl 1: 110-116.
4. Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet, 2009, 373(9678): 1905-1917.
5. Sher ER, Leung DY, Surs W, et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest, 1994, 93(1): 33-39.
6. Rodriguez JM, Monsalves-Alvarez M, Henriquez S, et al. Glucocorticoid resistance in chronic diseases. Steroids, 2016, 115: 182-192.
7. Herrlich P. Cross-talk between glucocorticoid receptor and AP-1. Oncogene, 2001, 20(19): 2465-2475.
8. Benetti C, Comberiati P, Capristo C, et al. Therapeutic effects of vitamin D in asthma and allergy. Mini Rev Med Chem, 2015, 15(11): 935-943.
9. Wu AC, Tantisira K, Li L, et al. Effect of vitamin D and inhaled corticosteroid treatment on lung function in children. Am J Respir Crit Care Med, 2012, 186(6): 508-513.
10. Chung J, Koyama T, Ohsawa M, et al. 1, 25(OH)₂D₃ blocks TNF-induced monocytic tissue factor expression by inhibition of transcription factors AP-1 and NF-κB. Lab Invest, 2007, 87(6): 540-547.
11. 刘瑶琦, 赵海金, 蔡绍曦. 补充维生素 D: 哮喘治疗新手段. 中国呼吸与危重监护杂志, 2016, 15(3): 305-309.
12. 宋颖芳, 洪景芳, 柳德灵,等. 1,25-二羟维生素 D3 对慢性哮喘小鼠气道重塑中 MMP-9 及 NF-κB 表达的影响. 中国呼吸与危重监护杂志, 2013, 12(1): 36-40.
13. 郝敏, 林江涛. 糖皮质激素抵抗性支气管哮喘诊治进展. 中华结核和呼吸杂志, 2014, 37(4): 296-298.
14. 孙永昌,罗慰慈. 激素抵抗型哮喘发生机制的研究. 国外医学呼吸系统分册, 1995, 15（2）: 58-60.
15. Karras SN, Shah I, Petroczi A, et al. An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: implications of a new assay on the roles of vitamin D forms. Nutr J, 2013, 12: 77.
16. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med, 2011, 364(3): 248-254.
17. Yao TC, Tu YL, Chang SW, et al. Serum 25-hydroxyvitamin D levels in relation to lung function and exhaled nitric oxide in children. J Pediatr, 2014, 165(6): 1098-1103. e1.
18. Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA, 2014, 311(20): 2083-2091.
19. Malinovschi A, Masoero M, Bellocchia M, et al. Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients. Respir Res, 2014, 15: 131.
20. Bantel H, Schmitz ML, Raible A, et al. Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsiveness. FASEB J, 2002, 16(13): 1832-1834.
21. Miraglia Del Giudice M, Allegorico A. The role of vitamin D in allergic diseases in children. J Clin Gastroenterol, 2016, 50 Suppl 2: S133-S135.

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Effect of 1,25-(OH)₂D₃ on JNK/AP-1 and glucocorticoid receptor of T lymphocytes in steroid-resistant asthmatics

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Effect of 1,25-(OH)₂D₃ on JNK/AP-1 and glucocorticoid receptor of T lymphocytes in steroid-resistant asthmatics