IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner.
Endothelial to mesenchymal transition (EndMT) contributes to fibrotic diseases. The main inducer of EndMT is TGFβ signaling. TGFβ2 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 TGFβ2-induced EndMT in the context of inflammatory IL-1β signaling. Co-stimulation with IL-1β and TGFβ2, but not TGFβ1, caused synergistic induction of EndMT. Also, TGFβ2 was the only TGFβ isoform that was progressively upregulated during EndMT. External IL-1β stimulation was dispensable once EndMT was induced. The inflammatory transcription factor NFκB was upregulated in an additive manner by IL-1β and TGFβ2 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-1β) and tissue remodeling (TGFβ2) can strongly promote the process of EndMT. Therefore our findings provide new insights into the mechanisms of pathological EndMT.
Department of Pathology and Medical Biology, Cardiovascular Regenerative Medicine Research Group, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Monika
M
Maleszewska
Jan-Renier A J
JR
Moonen
Nicolette
N
Huijkman
Bart
B
van de Sluis
Guido
G
Krenning
Martin C
MC
Harmsen
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D002467:Cell Nucleus / Q000276:immunology*; D060833:Cellular Microenvironment / Q000187:drug effects / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000276:immunology*; D005355:Fibrosis / Q000276:immunology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000276:immunology* / Q000494:pharmacology
C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; C508961:Tgfb1 protein, mouse; C509042:Tgfb2 protein, mouse; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2