新型含氮类固醇化合物选择性诱导PAM-212细胞胸腺基质淋巴生成素表达

IF 4.7 Q2 IMMUNOLOGY Journal of Translational Autoimmunity Pub Date : 2023-01-01 DOI:10.1016/j.jtauto.2022.100186
Yu Wang , Ryosuke Segawa , Yan Weng , Katsuya Nakai , Keiichiro Ohashi , Masahiro Hiratsuka , Mieko Arisawa , Noriyasu Hirasawa
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摘要

背景胸腺基质淋巴细胞生成素(TSLP)已被证明能够扩增Tregs。因此,TSLP诱导具有诱导内源性Tregs和控制自身免疫的潜力。在之前的研究中,我们发现一种名为02F04的新化合物可以诱导TSLP的产生,同时激活肝脏X受体(LXR)。由于LXR的激活会导致Treg的降低,我们试图找到一种02F04衍生物、可药用的铅化合物,该化合物具有基本骨架,可以在不激活LXR的情况下诱导TSLP的产生。结果,我们发现了HA-7和HA-19,并在本研究中检测了TSLP产生的分子机制。方法用HA-7和HA-19刺激小鼠角质形成细胞系PAM 212,然后用ELISA和实时荧光定量PCR检测细胞因子的表达。结果HA-7和HA-19诱导PAM212细胞产生TSLP,但几乎不表达TNF-α、IL-13、IL-25和IL-33。这些化合物抑制LXR活性。由HA-7和HA-19诱导的TSLP表达被Gq/11抑制剂YM-254890、ROCK抑制剂Y-27632和ERK抑制剂U0126抑制。HA-7和HA-19还诱导应激纤维的形成和ERK磷酸化,YM-254890和Y-27632抑制了这一过程。结论HA-7和HA-19通过Gq/11、Rho/ROCK和ERK途径选择性诱导PAM212产生TSLP。我们的研究结果还表明,TSLP的表达与其他细胞因子不同,并且低分子量化合物如HA-7和HA-19可以诱导选择性表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Selective induction of thymic stromal lymphopoietin expression by novel nitrogen-containing steroid compounds in PAM-212 cells

Background

Thymic stromal lymphopoietin (TSLP) has been shown to be able to amplify Tregs. Thus, TSLP induction has the potential to induce endogenous Tregs and control autoimmunity. In the previous research, we found that a new compound named 02F04 can induce TSLP production while simultaneously activating the liver X receptor (LXR). Because LXR activation leads to a decrease in Treg, we attempted to find a 02F04-derivative, druggable lead compound with a basic skeleton that induces TSLP production without activating LXR. As the results, we found HA-7 and HA-19 and, in this study, examined the molecular mechanisms in TSLP production.

Methods

A murine keratinocyte cell line PAM 212 was stimulated with HA-7 and HA-19, and then the expressions of cytokines were examined via ELISA and real-time fluorescence quantitative PCR.

Results

HA-7 and HA-19 induced TSLP production but almost not the expression of TNF-α, IL-13, IL-25, and IL-33 in PAM212 cells. These compounds inhibited LXR activities. The TSLP expression induced by HA-7 and HA-19 was inhibited by the Gq/11 inhibitor YM-254890, ROCK inhibitor Y-27632, and ERK inhibitor U0126. HA-7 and HA-19 also induced the formation of stress fiber and ERK phosphorylation, which were inhibited by YM-254890 and Y-27632.

Conclusions

Our findings indicated that HA-7 and HA-19 selectively induced TSLP production in PAM212 via Gq/11, Rho/ROCK and ERK pathways. Our findings also indicated that TSLP expression was differentially regulated from other cytokines, and the selective expression could be induced with low-molecular-weight compounds such as HA-7 and HA-19.

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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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