IL-1ß and TGFß2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner.

ABSTRACT

Endothelial to mesenchymal transition (EndMT) contributes to fibrotic diseases. The main inducer of EndMT is TGFß signaling. TGFß2 is the dominant isoform in the physiological embryonic EndMT, but its role in the pathological EndMT in the context of inflammatory co-stimulation is not known. The aim of this study was to investigate TGFß2-induced EndMT in the context of inflammatory IL-1ß signaling. Co-stimulation with IL-1ß and TGFß2, but not TGFß1, caused synergistic induction of EndMT. Also, TGFß2 was the only TGFß isoform that was progressively upregulated during EndMT. External IL-1ß stimulation was dispensable once EndMT was induced. The inflammatory transcription factor NFκB was upregulated in an additive manner by IL-1ß and TGFß2 co-stimulation. Co-stimulation also led to the nuclear translocation of NFκB which was sustained over long-term treatment. Activation of NFκB was indispensable for the co-induction of EndMT. Our data suggest that the microenvironment at the verge between inflammation (IL-1ß) and tissue remodeling (TGFß2) can strongly promote the process of EndMT. Therefore our findings provide new insights into the mechanisms of pathological EndMT.