5-HT2 and 5-HT2B antagonists attenuate pro-fibrotic phenotype in human adult dermal fibroblasts by blocking TGF-β1 induced non-canonical signaling pathways including STAT3 : implications for fibrotic diseases like scleroderma
- PMID:30207074
- DOI: 10.1111/1756-185X.13386
5-HT2 and 5-HT2B antagonists attenuate pro-fibrotic phenotype in human adult dermal fibroblasts by blocking TGF-β1 induced non-canonical signaling pathways including STAT3 : implications for fibrotic diseases like scleroderma
Abstract
Background: Release of 5-hydroxytryptamine (5-HT; serotonin) from activated platelets following microvascular injury leads to tissue fibrosis. 5-HT strongly induces extracellular matrix synthesis in dermal fibroblasts in a transforming growth factor beta 1 (TGF-β1)-dependent manner.
Aim: To evaluate anti-fibrotic properties of inhibitors of 5-HT2 and 5-HT2B (terguride, SB204741) respectively in human adult dermal fibroblasts (HADF) derived from a patient with scleroderma.
Methods: Anti-fibrotic efficacy of 5-HT2 and 5-HT2B inhibitors was evaluated as per two strategies: HADF were incubated with 5-HT (1 μM)/TGF-β1 (10 ng/mL) for 1 hour followed by 5-HT (1 μM)/TGF-β1 (10 ng/mL) and terguride or SB204741 (1 μM, each) for 24 hours (post-treatment strategy) and HADF were treated with terguride or SB204741 (1 μM, each) for 1 hour followed by 5-HT (1 μM)/TGF-β1 (10 ng/mL) for 24 hours (pre-treatment strategy). Real time quantitative polymerase chain reaction for expression of pro-fibrotic (TGFΒ1, COL1A1, COL1A2, ACTA2, CTGF and FN1) and anti-fibrotic genes (MMP2/TIMP1) was performed. Expression of type I collagen, alpha smooth muscle actin (α-SMA), phosphorylation of Smad3, ERK1/2 and STAT3 was examined by immunoblotting.
Results: Stimulation of HADF cells with 5-HT/TGF-β1 led to the increased expression of pro-fibrotic genes which was significantly reduced by both terguride and SB204741. Expression of anti-fibrotic genes was not affected upon incubation with the inhibitors. In 5-HT-stimulated HADF, treatment with terguride and SB204741 decreased type I collagen and α-SMA. In 5-HT/TGF-β1 stimulated HADF, terguride and SB204741 treatment reduced ERK1/2 and STAT3 phosphorylation but did not influence Smad3 phosphorylation.
Conclusion: Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-β1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders like scleroderma.
Keywords: Fibroblasts; STAT3; Serotonin; Serotonin antagonists; TGF-β1.
© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.
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