Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cellsPark, Kim, Choi
et alSci Rep (2021) 11 (1), 3196
Abstract: Activation of quiescent hepatic stellate cells (HSCs) to myofibroblasts plays a key role in liver fibrosis. We had previously shown that albumin and its derivative, R-III (a retinol-binding protein-albumin domain III fusion protein), inhibited HSC activation by sequestering retinoic acid (RA) and that R-III administration reduced carbon tetrachloride (CCl4)-induced liver fibrosis. In this study, we aimed to elucidate the mechanism of action of albumin downstream of RA sequestration. Nuclear factor-κB p65 was evenly distributed in the cytoplasm in activated mouse HSCs, whereas albumin expression or R-III treatment (albumin/R-III) caused the nuclear translocation of p65, probably via RA sequestration, resulting in a dramatic increase in interleukin-1beta (IL-1β) expression. Albumin/R-III in turn induced the phosphorylation of Smad3 at the linker region, inhibiting its nuclear import in an IL-1β-dependent manner. Consistent with the in vitro results, the level of IL-1β mRNA expression was higher in CCl4/R-III-treated livers than in CCl4-treated livers. These findings reveal that albumin/R-III inhibits the transforming growth factor-β-Smad3 signaling as well as the retinoic acid receptor-mediated pathway, which probably contributes to the inhibition of HSC activation, and suggest that R-III may be an anti-fibrotic drug candidate.
Therapeutic Effects of Anti-Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Treatment in Psoriasis and ArthritisAlvarez, Augustín, Tamayo
et alArthritis Rheumatol (2020) 72 (9), 1547-1558
Abstract: The transforming growth factor β (TGFβ) inhibitor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGFβ and interleukin-2 (IL-2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti-BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease.Development of Saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n = 18-30 mice per group), imiquimod-induced skin psoriasis (n = 20-30 mice per group), or type II collagen-induced arthritis (CIA) (n = 13-16 mice per group) was analyzed in a total of 2-5 different experiments with either wild-type (WT) or BAMBI-deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti-BAMBI), a mouse IgG1 anti-TNP isotype control, anti-CD25, or anti-TGFβ mAb.Treatment of normal mice with IgG1 anti-BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL-17-producing cells, and was dependent on the level of TGFβ activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti-BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls).These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.© 2020, American College of Rheumatology.
Reduced matrix metalloproteinase and collagen transcription mediated by the TGF-β/Smad pathway in passaged normal human dermal fibroblastsKim, Kim, Ahn
et alJ Cosmet Dermatol (2020) 19 (5), 1211-1218
Abstract: Transforming growth factor-β (TGF-β) is a major regulator of extracellular matrix (ECM) events, particularly collagen production.We explored whether the expression of matrix metalloproteinases (MMPs) and collagen are transcriptionally regulated by the TGF-β and Smad signaling pathways, and the roles played by NF-κB and mitogen-activated protein kinase (MAPK) signaling in normal, aged, human dermal fibroblasts.We quantified mRNA and protein expression using real-time PCR and immunoblotting of proteins from cells in passage 5-15.The levels of mRNAs encoding TGF-β1, TGF-β3, and TGF-β receptor type I (TGFβ RI) decreased with increasing passage number. The levels of mRNAs encoding TGF-β2, TGFβ RII, and TGFβ RIII increased to passage 10 but decreased by passage 15. The levels of mRNAs encoding Smad-2, -3, -4, and -7 decreased with increasing passage number. The level of mRNA encoding MMP-1 increased with increasing passage number, and the levels of mRNAs encoding MMP-2, TIMP-1, and TIMP-2 increased to passage 10 but decreased by passage 15. The levels of mRNAs encoding collagen types I and II decreased with increasing passage number. At the protein level, NF-κB, IκBα, p38, ERK, Akt, and JNK became increasingly phosphorylated at higher passage numbers.Our results suggest that reductions in the expression levels of MMPs and collagen types I and III in aging human dermal fibroblasts reflect reduced expression of TGF-β/Smad and TGF-β receptors, thus compromising the TGF-β receptor-binding capacity of fibroblasts; the NF-κB and Akt-JNK/MAPK signaling pathways may play active roles in this process.© 2019 Wiley Periodicals, Inc.
[Comparison study on the differential expression of miRNAs in rat pulmonary fibrosis induced by nanosized SiO(2) and microsized SiO(2)]Yang, Li, Li
et alZhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi (2019) 37 (2), 81-89
Abstract: Objective: To explore the correlation between expression level of miRNAs and pulmonary fibrosis on the basis of comparison the differential expression of miRNAs in rat pulmonary fibrosis induced by nano SiO(2) and micron SiO(2). Methods: Thirty-six healthy male SD rats weighting 180-220 g were randomly divided into 3 groups. They were instilled intratracheally with 1 ml suspension of saline, 25 mg/ml nanosized SiO(2) and microsized SiO(2) particles and sacrificed at 60 d and 90 d postexposure from each group with six rats. The change of pathological morphology and ultrastructure of lung were observed by optical and transmission electron microscopy. The differentially expressed microRNAs in lung tissue of the rats after instilled intrachcally nanosized SiO(2) and microsized SiO(2) particles at 60 d and 90 d were determined by Illumina HiSeq 2 000 sequencing technique. Target prediction for miRNAs was conducted by databases of Target-scan. Function-significant enrichment analysis and signal pathway analysis for predicted target genes were respectively conducted by the GO and the KEGG, then target genes related to pulmonary fibrosis were screened out. Results: Light microscope examination showed that wide bronchi, vessels, interlobular septa and slight fibrous connective tissue proliferation at 60 d and 90 d postexposure in 25 mg/ml nanosized SiO(2) group. A few fused nodules at 30 d postexposure, a lot of fused nodules at 60 d postexposure, fibrous cell nodules and compensatory emphysema around alveolar at 90 d postexposure in 25 mg/mL microsized SiO(2) group were observed. Electron microscopy demonstrated swelling and vacuolar degeneration of osmiophilic lamellar bodies in type Ⅱ alveolar epithelial cells, collagen fiber and elastic fiber hyperplasia in pulmonary interstitial at 60 d, 90 d postexposure in 25 mg/ml nanosized SiO(2) group. Increased and vacuoloid changed osmiophilic lamellar bodies in type Ⅱ alveolar epithelial cells, collagen fiber and elastic fiber hyperplasia in the interstitial at 60 d, 90 d postexposure in 25 mg/ml microsized SiO(2) group were observed. Comparing to saline control group, the number of miRNA up-regulated expression was 50, 70, and down-regulated expression was 22 and 24 at 60 d, 90 d postexposure in 25 mg/ml nanosized SiO(2) group respectively. There were 91,70 miRNAs up-regulated expression and 34,78 miRNAs down-regulated expression at 60 d, 90 d postexposure in 25 mg/ml microscale SiO(2) group. The common miRNA of differential up-regulated expression are miRNA-18a and miRNA-702-3p, down-regulated expression are miRNA-541, miRNA-127 and miRNA-379 both in nanosized SiO(2) and microscale SiO(2) group. The target genes related to pulmonary fibrosis were CTGF, IGF, BMP7, FGF7, TGF-β RIII, IGF1R and TGF-β1 respectively. Their biologic functions are to regulate signal pathway of TGF-β, MAPK and Wnt, and activation of fibroblast. Conclusion: These findings suggested that same dose of nanosized SiO(2) particles could cause mainly characterized by pulmonary interstitial fibrosis differing from silicotic nodule caused by microsized SiO(2). miRNA-18a, miRNA-702-3p, miRNA-541, miRNA-127 and miRNA-379 may play a role in the process of pulmonary fibrosis in nanosized SiO(2) and microscale SiO(2) by regulating its target genes.
膜杰作
Star Staining
