Background

The mouse lung telocyte cell line (TC^SV40) recently established provides further opportunities to learn TC biology and functions. The present study aims at investigating regulatory roles of phosphoinositide 3-kinase (PI3K) isoforms in TC proliferation and movement and in TGFβ1-induced sensitivity and response of lung TCs to PI3K inhibitors.

Materials and methods

Network and molecular interactions of genes coding PI3K family or TGFβ family proteins in mouse primary TCs were defined. Mouse lung TC^SV40 proliferation, apoptosis, cell cycle, and dynamical bio-behaviors were measured with or without TGFβ1 stimulation or PI3K catalytic isoform protein (PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K) inhibitions.

Results

The present study showed the difference of network characteristics and interactions of genes coding PI3K isoform proteins or TGFβ family proteins in primary lung telocytes from mouse lungs compared to those of other cells residing in the lung. TGFβ1 had diverse effects on TC proliferation with altered TC number in G2 or S phase, independent upon the administered dose of TGFβ1. PI3Kα/δ/β, PI3K/mTOR, and PI3K p110δ were involved in TC proliferation, of which PI3Kα/δ/β was more sensitive. The effects of pan-PI3K inhibitor indicate that more PI3K isoforms were stimulated by the administering of external TGFβ1 and contributed to TGFβ1-induced TC proliferation. PI3K p110δ upregulated TC proliferation and movement dynamically without TGFβ1, and downregulated TC proliferation with TGFβ1 stimulation, but not TC movement. PI3Kα/δ/β and PI3K/mTOR were more active in TGFβ1-induced S phase accumulation and had similar dynamic effects to PI3K p110δ. Gene expression of PI3K isoforms in TCs was upregulated after TGFβ1 stimulation. The expression of PIK3CA coding p110-α or PIK3CG coding p110-γ were up- or downregulated in TCs without TGFβ1, respectively, when PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K were inhibited. TGFβ1 upregulated the expression of PIK3CA and PIK3CB, while downregulated the expression of PIK3CD and PIK3CG.

Conclusion

Our data imply that TGFβ1 plays divergent roles in the expression of PI3K isoform genes in lung TCs and can alter the sensitivity and response of lung TCs to PI3K inhibitors.

中文翻译：

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TGFβ1在磷酸肌醇3激酶同工型基因的表达中的作用，以及肺细胞对PI3K抑制剂的敏感性和应答。

背景

最近建立的小鼠肺telocyte细胞系（TC ^SV40）为学习TC生物学和功能提供了进一步的机会。本研究旨在调查磷酸肌醇3-激酶（PI3K）亚型在TC增殖和运动以及TGFβ1诱导的肺TC对PI3K抑制剂的敏感性和反应中的调节作用。

材料和方法

定义了小鼠初级TC中编码PI3K家族或TGFβ家族蛋白的基因的网络和分子相互作用。在有或没有TGFβ1刺激或PI3K催化亚型蛋白（PI3K / mTOR，PI3Kα/δ/β，PI3Kp110δ或pan-PI3K）抑制的情况下，测量了小鼠肺TC ^SV40的增殖，凋亡，细胞周期和动态生物行为。

结果

本研究表明，与肺中其他细胞相比，小鼠肺原代肺细胞中的网络特性和编码PI3K同工型蛋白或TGFβ家族蛋白的基因相互作用的差异。TGFβ1对TC增殖具有多种影响，在G2或S期中TC数发生变化，而与TGFβ1的给药剂量无关。PI3Kα/δ/β，PI3K / mTOR和PI3Kp110δ参与了TC的增殖，其中PI3Kα/δ/β更为敏感。pan-PI3K抑制剂的作用表明，通过施用外部TGFβ1可以刺激更多的PI3K亚型，并有助于TGFβ1诱导的TC增殖。PI3Kp110δ在没有TGFβ1的情况下动态上调TC增殖和运动，而在TGFβ1刺激下下调TC增殖，但没有TC运动。PI3Kα/δ/β和PI3K / mTOR在TGFβ1诱导的S期积累中更活跃，并且具有与PI3Kp110δ类似的动力学作用。TGFβ1刺激后TCs中PI3K同工型的基因表达上调。当PI3K / mTOR，PI3Kα/δ/β，PI3Kp110δ或pan-PI3K受到抑制时，在没有TGFβ1的TC中，分别编码p110-α的PIK3CA或p110-γ的PIK3CG的表达上调或下调。TGFβ1上调PIK3CA和PIK3CB的表达，而下调PIK3CD和PIK3CG的表达。或pan-PI3K被抑制。TGFβ1上调PIK3CA和PIK3CB的表达，而下调PIK3CD和PIK3CG的表达。或pan-PI3K被抑制。TGFβ1上调PIK3CA和PIK3CB的表达，而下调PIK3CD和PIK3CG的表达。

结论

我们的数据表明，TGFβ1在肺TC中的PI3K亚型基因表达中起着不同的作用，并且可以改变肺TC对PI3K抑制剂的敏感性和反应。