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白细胞介素-13/干扰素-γ平衡的改变导致干燥综合征CD25基因敲除模型中泪腺破坏和分泌功能障碍。

Altered balance of interleukin-13/interferon-gamma contributes to lacrimal gland destruction and secretory dysfunction in CD25 knockout model of Sjögren's syndrome.

作者信息

Bian Fang, Barbosa Flavia L, Corrales Rosa M, Pelegrino Flavia S A, Volpe Eugene A, Pflugfelder Stephen C, de Paiva Cintia S

机构信息

Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin Street, NC505G, Houston, TX 77030, Texas, USA.

出版信息

Arthritis Res Ther. 2015 Mar 10;17(1):53. doi: 10.1186/s13075-015-0582-9.

DOI:10.1186/s13075-015-0582-9
PMID:25889094
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4392623/
Abstract

INTRODUCTION

The lacrimal gland (LG) of the CD25-/- model of Sjögren's syndrome (SS) has high interleukin (IL)-17, IL-13 and interferon-gamma (IFN-γ) cytokines. The specific contribution of these cytokines to the onset and severity of dacryoadenitis in the CD25-/- mice has not been evaluated.

METHODS

CD25-/-IL-17A-/-, CD25-/-IL-17-/-IFN-γ-/- and CD25-/-IFN-γ-/- were used at 4, 8, 12, 16 weeks (W). Total lymphocytic infiltration was evaluated by histology and characterized by flow cytometry. Epidermal growth factor (EGF) concentration was measured in tears. Immunofluorescent staining evaluated expression of IFN-γ receptor (IFN-γR) and apoptosis. Real-time PCR evaluated inflammatory and T cell-related cytokines expression in LG. Caspase-3, -8, -9 activities was assayed in LG lysates. T helper cytokines were measured in serum by Luminex assay.

RESULTS

The greatest total LG infiltration at 8 W was seen in CD25-/-IL-17A-/- (95%), followed by CD25-/- (71%) and IL-17-/- (12%). Tear EGF concentration was in normal range in CD25-/- at 4 W and in very low levels in both CD25-/- and CD25-/-IL-17A-/-. CD25-/- had high levels of inflammatory cytokines transcripts in LG compared to IL-17-/- mice; however, CD25-/-IL-17A-/- had even higher IL-1β, IFN-γR, caspase-3, -8, -9 mRNA levels, greater immunoreactivity to IFN-γR in LG acini, greater number of apoptotic+ cells and greater caspases activities in the LG at 8 W. CD25-/-IL-17A-/- had lower IL-13 concentration and lower IL-13/IFN-γ ratio compared to CD25-/- in serum. CD25-/-IFN-γ-/- had lower number of apoptotic+ cells and decreased caspase-3 expression in LG. CD25-/-IL-17-/-IFN-γ-/- had lower total lymphocytic cell infiltration at 8 W (48%), CD4+T cell infiltration and expression of IFN-γR and apoptotic+ cells in the LG and increased tear EGF concentration in tears.

CONCLUSIONS

IFN-γ is critical for LG destruction and secretory dysfunction in the CD25-/- model of SS. Altered balance between IFN-γ and IL-13 in the CD25-/-IL-17A-/- mice accelerates LG destruction by increasing glandular apoptosis and facilitating apoptosis through increased expression of IFN-γR by glandular epithelium and activation of caspases. Targeting both IFN-γ and IL-17 may be beneficial for treating the LG inflammation in SS.

摘要

引言

干燥综合征（SS）的CD25 - / - 模型的泪腺（LG）具有高水平的白细胞介素（IL）-17、IL-13和干扰素-γ（IFN-γ）细胞因子。这些细胞因子对CD25 - / - 小鼠泪腺炎的发病和严重程度的具体作用尚未评估。

方法

在4、8、12、16周（W）使用CD25 - / - IL-17A - / - 、CD25 - / - IL-17 - / - IFN-γ - / - 和CD25 - / - IFN-γ - / - 小鼠。通过组织学评估总淋巴细胞浸润，并通过流式细胞术进行表征。测量泪液中表皮生长因子（EGF）浓度。免疫荧光染色评估IFN-γ受体（IFN-γR）的表达和细胞凋亡。实时PCR评估泪腺中炎症和T细胞相关细胞因子的表达。测定泪腺裂解物中半胱天冬酶-3、-8、-9的活性。通过Luminex测定法测量血清中的辅助性T细胞细胞因子。

结果

在8周时，CD25 - / - IL-17A - / - 小鼠的泪腺总浸润程度最高（95%），其次是CD25 - / - 小鼠（71%）和IL-17 - / - 小鼠（12%）。CD25 - / - 小鼠在4周时泪液EGF浓度在正常范围内，而CD25 - / - 和CD25 - / - IL-17A - / - 小鼠的泪液EGF浓度都非常低。与IL-17 - / - 小鼠相比，CD25 - / - 小鼠泪腺中炎症细胞因子转录物水平较高；然而，CD25 - / - IL-17A - / - 小鼠在8周时IL-1β、IFN-γR、半胱天冬酶-3、-8、-9的mRNA水平更高，泪腺腺泡中对IFN-γR的免疫反应性更强，凋亡阳性细胞数量更多，泪腺中的半胱天冬酶活性更高。与CD25 - / - 小鼠相比，CD25 - / - IL-17A - / - 小鼠血清中的IL-13浓度更低，IL-13/IFN-γ比值更低。CD25 - / - IFN-γ - / - 小鼠泪腺中凋亡阳性细胞数量更少，半胱天冬酶-3表达降低。CD25 - / - IL-17 - / - IFN-γ - / - 小鼠在8周时总淋巴细胞浸润程度更低（48%），泪腺中CD4 + T细胞浸润、IFN-γR表达和凋亡阳性细胞减少，泪液中EGF浓度升高。

结论

在SS的CD25 - / - 模型中，IFN-γ对泪腺破坏和分泌功能障碍至关重要。CD25 - / - IL-17A - / - 小鼠中IFN-γ和IL-13之间平衡的改变通过增加腺泡凋亡以及通过腺泡上皮细胞中IFN-γR表达增加和半胱天冬酶激活促进凋亡，加速了泪腺破坏。同时靶向IFN-γ和IL-17可能有利于治疗SS中的泪腺炎症。

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