Roles of TGFß1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors.

BACKGROUND: The mouse lung telocyte cell line (TCSV40) 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 TGFß1-induced sensitivity and response of lung TCs to PI3K inhibitors. MATERIALS AND METHODS: Network and molecular interactions of genes coding PI3K family or TGFß family proteins in mouse primary TCs were defined. Mouse lung TCSV40 proliferation, apoptosis, cell cycle, and dynamical bio-behaviors were measured with or without TGFß1 stimulation or PI3K catalytic isoform protein (PI3K/mTOR, PI3Kα/δ/ß, 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 TGFß family proteins in primary lung telocytes from mouse lungs compared to those of other cells residing in the lung. TGFß1 had diverse effects on TC proliferation with altered TC number in G2 or S phase, independent upon the administered dose of TGFß1. PI3Kα/δ/ß, PI3K/mTOR, and PI3K p110δ were involved in TC proliferation, of which PI3Kα/δ/ß was more sensitive. The effects of pan-PI3K inhibitor indicate that more PI3K isoforms were stimulated by the administering of external TGFß1 and contributed to TGFß1-induced TC proliferation. PI3K p110δ upregulated TC proliferation and movement dynamically without TGFß1, and downregulated TC proliferation with TGFß1 stimulation, but not TC movement. PI3Kα/δ/ß and PI3K/mTOR were more active in TGFß1-induced S phase accumulation and had similar dynamic effects to PI3K p110δ. Gene expression of PI3K isoforms in TCs was upregulated after TGFß1 stimulation. The expression of PIK3CA coding p110-α or PIK3CG coding p110-γ were up- or downregulated in TCs without TGFß1, respectively, when PI3K/mTOR, PI3Kα/δ/ß, PI3K p110δ, or pan-PI3K were inhibited. TGFß1 upregulated the expression of PIK3CA and PIK3CB, while downregulated the expression of PIK3CD and PIK3CG. CONCLUSION: Our data imply that TGFß1 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.