JAK1/JAK2抑制剂外用对特应性皮炎小鼠模型的影响
|
摘要
目的观察JAK1/JAK2抑制剂外用对特应性皮炎(atopic dermatitis,AD)小鼠模型的影响并探讨其作用机制。方法将18只BALB/C小鼠随机分为正常组、模型组、治疗组。模型组及治疗组应用2,4-二硝基氯苯诱导AD模型后,皮损处分别涂抹不含JAK1/JAK2抑制剂的空白软膏、JAK1/JAK2抑制剂软膏,连续涂抹14天。正常组仅脱毛,不给予任何治疗。实验第28天肉眼观察各组小鼠背部皮损处表现;HE染色观察皮损组织病理形态;ELISA法检测血清IgE水平;RT-qPCR法检测皮损组织IL-4、IL-5、IFN-γ mRNA表达。结果治疗组背部皮损处表现及组织病理形态较模型组明显改善,血清IgE含量明显减低,皮损组织IL-4、IL-5、IFN-γ mRNA相对表达量明显减少。结论 JAK1/JAK2抑制剂外用对AD小鼠模型具有较好的治疗作用,其机制之一可能与抑制皮损组织IL-4、IL-5、IFN-γ mRNA表达相关。
Objective To observe the effect of topical Jak1/Jak2 inhibitor on atopic dermatitis(AD) mice model and to explore its mechanism. Methods Eighteen BALB/C mice were randomly divided into normal group,model group,and treatment group. After the model group and the treatment group were treated with 2,4-dinitrochlorobenzene to induce the AD model,the skin lesions were coated with a blank ointment containing no JAK1/JAK2 inhibitor and a JAK1/JAK2 inhibitor ointment for 14 days. The normal group only had hair removed and no treatment was given. On the 28 th day of the experiment,the appearance of the skin lesions on the back of each group was observed;the histopathological changes of lesions was observed by HE staining;the serum IgE level was detected by ELISA,and the expressions of IL-4,IL-5 and IFN-γ mRNA in the lesions were detected by RT-qPCR. Results In the treatment group,the appearance and histopathological changes of the lesions improved significantly,the serum IgE content decreased significantly,and the relative expression of IL-4,IL-5,IFN-γ mRNA in the lesions decreased significantly. Conclusion The topical use of JAK1/JAK2 inhibitor has a good therapeutic effect on the AD mice model,and one of the mechanisms may be related to the inhibition of IL-4,IL-5 and IFN-γ mRNA expression in lesional tissues.
Objective To observe the effect of topical Jak1/Jak2 inhibitor on atopic dermatitis(AD) mice model and to explore its mechanism. Methods Eighteen BALB/C mice were randomly divided into normal group,model group,and treatment group. After the model group and the treatment group were treated with 2,4-dinitrochlorobenzene to induce the AD model,the skin lesions were coated with a blank ointment containing no JAK1/JAK2 inhibitor and a JAK1/JAK2 inhibitor ointment for 14 days. The normal group only had hair removed and no treatment was given. On the 28 th day of the experiment,the appearance of the skin lesions on the back of each group was observed;the histopathological changes of lesions was observed by HE staining;the serum IgE level was detected by ELISA,and the expressions of IL-4,IL-5 and IFN-γ mRNA in the lesions were detected by RT-qPCR. Results In the treatment group,the appearance and histopathological changes of the lesions improved significantly,the serum IgE content decreased significantly,and the relative expression of IL-4,IL-5,IFN-γ mRNA in the lesions decreased significantly. Conclusion The topical use of JAK1/JAK2 inhibitor has a good therapeutic effect on the AD mice model,and one of the mechanisms may be related to the inhibition of IL-4,IL-5 and IFN-γ mRNA expression in lesional tissues.
引文
[1]Bieber T.Atopic Dermatitis[J].Annal Dermatol,2010,22(2):125.
[2]Lei B,Zhang H,Chan LS.The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis[J].JAK-STAT,2013,2(3):13-16.
[3]Damsky W,King BA.JAK inhibitors in dermatology:The promise of a new drug class[J].J Am Acad Dermatol,2017,76(4):736-744.
[4]Verstovsek S,Courby S,Griesshammer M,et al.A phase 2study of momelotinib,a potent JAK1 and JAK2 inhibitor,in patients with polycythemia vera or essential thrombocythemia[J].Leukemia Res,2017,60:11-17.
[5]Banerjee S,Biehl A,Gadina M,et al.Erratum to:JAK-STAT signalling as a target for inflammatory and autoimmune diseases:current and future prospects[J].Drugs,2017,77(5):11.
[6]Villarino AV,Kanno Y,Ferdinand J R,et al.Mechanisms of JAK/STAT signaling in immunity and disease[J].J Immunol,2015,194(1):21-27.
[7]O'Shea JJ,Plenge R.JAK and STAT signaling molecules in immunoregulation and immune-mediated disease[J].Immunity,2012,36(4):542.
[8]Furue M,Chiba T,Tsuji G,et al.Atopic dermatitis:immune deviation,barrier dysfunction,Ig E autoreactivity and new therapies[J].Allergol Int,2017,66(3):398-403.
[9]Welsch K,Holstein J,Laurence A,et al.Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors[J].Eur J Immunol,2017,47(7):1096.
[10]Nomura T,Kabashima K.Advances in atopic dermatitis in2015[J].J Allergy Clin Immunol,2016,138(6):1548-1555.
[11]Bao L,Shi VY,Chan LS.IL-4 regulates chemokine CCL26in keratinocytes through the Jak1,2/Stat6 signal transduction pathway:Implication for atopic dermatitis[J].Mol Immunol,2012,50(1-2):91-97.
[12]Amano W,Nakajima S,Kunugi H,et al.The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription3 signaling[J].J Allergy Clin Immunol,2015,136(3):667-677.
[2]Lei B,Zhang H,Chan LS.The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis[J].JAK-STAT,2013,2(3):13-16.
[3]Damsky W,King BA.JAK inhibitors in dermatology:The promise of a new drug class[J].J Am Acad Dermatol,2017,76(4):736-744.
[4]Verstovsek S,Courby S,Griesshammer M,et al.A phase 2study of momelotinib,a potent JAK1 and JAK2 inhibitor,in patients with polycythemia vera or essential thrombocythemia[J].Leukemia Res,2017,60:11-17.
[5]Banerjee S,Biehl A,Gadina M,et al.Erratum to:JAK-STAT signalling as a target for inflammatory and autoimmune diseases:current and future prospects[J].Drugs,2017,77(5):11.
[6]Villarino AV,Kanno Y,Ferdinand J R,et al.Mechanisms of JAK/STAT signaling in immunity and disease[J].J Immunol,2015,194(1):21-27.
[7]O'Shea JJ,Plenge R.JAK and STAT signaling molecules in immunoregulation and immune-mediated disease[J].Immunity,2012,36(4):542.
[8]Furue M,Chiba T,Tsuji G,et al.Atopic dermatitis:immune deviation,barrier dysfunction,Ig E autoreactivity and new therapies[J].Allergol Int,2017,66(3):398-403.
[9]Welsch K,Holstein J,Laurence A,et al.Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors[J].Eur J Immunol,2017,47(7):1096.
[10]Nomura T,Kabashima K.Advances in atopic dermatitis in2015[J].J Allergy Clin Immunol,2016,138(6):1548-1555.
[11]Bao L,Shi VY,Chan LS.IL-4 regulates chemokine CCL26in keratinocytes through the Jak1,2/Stat6 signal transduction pathway:Implication for atopic dermatitis[J].Mol Immunol,2012,50(1-2):91-97.
[12]Amano W,Nakajima S,Kunugi H,et al.The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription3 signaling[J].J Allergy Clin Immunol,2015,136(3):667-677.