5-HT<sub>2</sub> and 5-HT<sub>2B</sub> 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.
This study shows that the increased number of macrophages with heterogeneous immunophenotypes, which might be induced by MCP-1 and CSF-1, could participate in the sclerotic lesion formation, presumably through increased fibrogenic factors such as galectin-3 and TGF-β1; the data may provide useful information to understand the pathogenesis of the human scleroderma condition.
We found that bp -532 to -521 on the VEGF promoter is a putative binding site for Smads, and that the binding activity of Smad3 to VEGF promoter was constitutively increased in SSc fibroblasts as well as in normal fibroblasts treated with exogenous TGF-β1.
The applicability of these findings to TGFβ1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease (ILD).
The aim of this study was to examine c-Ski and SnoN, principal molecules in the negative regulation of TGFbeta signaling, to further understand the autocrine TGFbeta loop in scleroderma.
Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFbeta1 and TGFbeta2.
Transforming growth factor beta1 (TGFbeta1) is a profibrotic cytokine that stimulates excessive collagen production in patients with scleroderma or other fibrotic diseases.
Furthermore, FKBP12, which protects TGFbeta receptor type I from ligand-independent activation by TGFbeta receptor type II, constitutively dissociated from TGFbeta receptor type I in scleroderma fibroblasts.
In this study, we focused on the alpha(v)beta3 integrin, which is recently demonstrated to function as an active receptor for latent TGF-beta1 through its interaction with latency-associated peptide-beta1, and investigated the involvement of this integrin in the pathogenesis of scleroderma.
TGF-beta blocking antibody or TGF-beta1 antisense oligonucleotide markedly reduced the up-regulated TSP-1 expression in scleroderma fibroblasts but had little effect on normal fibroblasts.
These analyses also revealed that this treatment significantly reduced both the expression of the TGF-beta1 mRNA and the production of TGF-beta1 on macrophage-like cells that infiltrated the dermis and the fibroblastic cells in BLM-induced scleroderma.
PDGF alpha receptor protein levels correlated directly with mRNA levels, induced by bFGF only in healthy fibroblasts and by TGF-beta 1 only in scleroderma fibroblasts.
Using constructs (COL1A2/CAT) containing the promoter for the alpha 2 (I) collagen gene in transient transfection assays with matched pairs of scleroderma and normal skin fibroblasts, we observed higher transcriptional activity of the COL1A2 gene in scleroderma fibroblasts and, in contrast to normal fibroblasts, no further expression was observed in the presence of TGF beta 1.