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Warren S L Liao - One of the best experts on this subject based on the ideXlab platform.
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transcription factor ap 2 functions as a repressor that contributes to the liver specific expression of Serum Amyloid A1 gene
Journal of Biological Chemistry, 2001Co-Authors: Warren S L LiaoAbstract:Abstract We previously identified transcription factor AP-2 as the nuclear factor that interacts with the tissue-specific repressor element in the rat Serum Amyloid A1 (SAA1) promoter. In this report, we provide evidence for a second AP-2-binding site and show that both AP-2 sites participate in mediating the transcription repression of SAA1 promoter. This proximal AP-2 site overlaps with the NFκB-binding site known to be essential for SAA1 promoter activity. Protein binding competition experiments demonstrated that AP-2 and NFκB binding to these overlapping sites were mutually exclusive. Furthermore, the addition of AP-2 easily displaced prebound NFκB, whereas NFκB could not displace AP-2. These results thus suggest that one mechanism by which AP-2 negatively regulates SAA1 promoter activity may be by antagonizing the function of NFκB. Consistent with a repression function, transient expression of AP-2 in HepG2 cells inhibited conditioned medium-induced SAA1 promoter activation. This inhibition was dependent on functional AP-2-binding sites, since mutation of AP-2-binding sites abolished inhibitory effects of AP-2 in HepG2 cells as well as resulted in derepression of the SAA1promoter in HeLa cells. In addition to SAA1, we found that several other liver gene promoters also contain putative AP-2-binding sites. Some of these sequences could specifically inhibit AP-2·DNA complex formation, and for the human complement C3 promoter, overexpression of AP-2 also could repress its cytokine-mediated activation. Finally, stable expression of AP-2 in hepatoma cells significantly reduced the expression of endogenous SAA, albumin, and α-fetoprotein genes. Taken together, our results suggest that AP-2 may function as a transcription repressor to inhibit the expression of not only SAA1 gene but also other liver genes in nonhepatic cells.
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purification and identification of a tissue specific repressor involved in Serum Amyloid A1 gene expression
Journal of Biological Chemistry, 1999Co-Authors: Shrikanth A G Reddy, Warren S L LiaoAbstract:Abstract We have previously demonstrated that the 5′-flanking regions from the rat Serum Amyloid A1 (SAA1) promoter are necessary and sufficient to confer specific cytokine-induced expression in cultured hepatoma cells. Deletion analysis identified a tissue-specific repressor (TSR) regulatory element, located between bp −289 and −256, that functioned as a silencer, contributing to the transcription repression on SAA1 promoter in nonliver cells. When this 34-base pair TSR-binding element was used as a probe in electrophoretic mobility shift assays, an intense DNA-protein complex was detected in nuclear extracts from HeLa and several other nonliver tissues. This TSR binding activity, however, was undetectable in extracts from liver or liver-derived cells. The distribution of TSR binding activity is therefore consistent with its regulatory role in repressing SAA1 expression in a tissue-specific manner. In this study, we purified TSR protein from HeLa nuclear extracts and showed that it has a molecular mass of approximately 50 kDa. Surprisingly, protein sequencing and antibody supershift experiments identified TSR as transcription factor AP-2. Subsequent functional analysis showed that forced expression of AP-2 in HepG2 cells could indeed inhibit conditioned medium-induced SAA1 promoter activation. Moreover, expression of a dominant-negative mutant of AP-2 in HeLa cells or mutation of the AP-2-binding site led to derepression of the SAA1 promoter, presumably by neutralizing the inhibitory effects of the endogenous wild-type AP-2. Our results therefore demonstrate a novel function for AP-2 in the transcriptional repression of SAA1 promoter. Together with its tissue distribution, AP-2 may contribute to SAA1's highly liver-specific expression pattern by restricting its expression in nonliver cells.
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an upstream repressor element that contributes to hepatocyte specific expression of the rat Serum Amyloid A1 gene
Biochemical and Biophysical Research Communications, 1999Co-Authors: Lei Li, Warren S L LiaoAbstract:Abstract Serum Amyloid A (SAA) is a major acute-phase protein whose expression can be dramatically induced in response to tissue damage, infection, and inflammation. Its expression is highly tissue-specific, restricted almost exclusively to liver hepatocytes. We have shown that a 320-bp fragment of the rat SAA1 promoter could confer liver-cell-specific expression on a reporter gene when transfected into cultured cells. Here we report the identification of a 29-bp regulatory element that possesses inhibitory activities on SAA1 promoter in HeLa cells but has no such effects in liver cells. Moreover, this regulatory element has properties of a transcriptional repressor; in that, it can function with a heterologous promoter and is independent of orientation and distance from the transcription initiation site. Protein binding studies showed that this regulatory element can form specific protein–DNA complexes with nuclear proteins from several nonliver cell lines (HeLa, 10T1/2, and C2) and placenta. However, the same DNA–protein complex was not detected in extracts from liver or liver-derived cell lines (HepG2 and Hep3B). Taken together, our results demonstrate the presence of a DNA-binding protein, termed tissue-specific repressor, found only in nonhepatocytes which may function to repress SAA1 gene expression by interacting with a repressor element. Thus, liver-specific expression of the SAA1 gene is apparently regulated by both positive and negative regulatory elements and their interacting transcription factors to ensure that it is expressed only in suitable cell types.
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yy1 represses rat Serum Amyloid A1 gene transcription and is antagonized by nf kappa b during acute phase response
Molecular and Cellular Biology, 1994Co-Authors: Szu Yao Lu, Maria A Rodriguez, Warren S L LiaoAbstract:Abstract Serum Amyloid A (SAA), one of the major acute-phase proteins, increases several hundredfold in concentration in plasma following acute inflammation, primarily as a result of a 200-fold increase in its transcriptional rate. Functional analysis of the rat SAA1 promoter has identified a 65-bp cytokine response unit (CRU; positions -135 to -71) that could confer cytokine responsiveness on a heterologous promoter. Within this CRU, two cis-regulatory elements, corresponding to NF-kappa B- and C/EBP-binding sites, were found to be functionally important and exerted synergistic effects on induced SAA1 expression. In this report, we show that a third transcription factor interacts with the CRU through a region located between the NF-kappa B- and C/EBP-binding sites. On the basis of its gel mobility shift patterns, ubiquitous binding activity, sequence specificity of DNA binding, zinc-dependent binding activity, and gel mobility supershift by specific antibodies, we concluded that this factor is identical to YY1. Methylation interference studies revealed that YY1 binding sequences overlapped with those of NF-kappa B, and gel mobility studies showed that NF-kappa binding to the CRU was effectively inhibited by YY1. Consistent with its presumed antagonistic role to NF-kappa B, YY1 exerted a negative effect on SAA1 expression, whereas disruption of its binding in the promoter elevated basal and cytokine-induced activities. Furthermore, overexpression of YY1 trans-repressed SAA1 promoter activity. Thus, our results demonstrate that SAA1 expression is tightly regulated by an on-off switch of activators and repressors, presumably to ensure that it is expressed only under appropriate physiological conditions.
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cooperative effects of c ebp like and nfxb like binding sites on rat Serum Amyloid A1 gene expression in liver cells
Nucleic Acids Research, 1992Co-Authors: Xiaoxia Li, Warren S L LiaoAbstract:Serum Amyloid A (SAA) is a major acute-phase protein synthesized and secreted mainly by the liver. In response to inflammation, its expression is increased by 1000-fold, primarily because of a 200-fold increase in the rates of SAA gene transcription. We have shown that when 304 bp of 5' flanking region of the rat SAA1 gene is fused to a reporter gene, the chloramphenicol acetyltransferase (CAT) gene, CAT activity is induced in a cell-specific manner in response to conditioned media prepared from activated mixed lymphocyte cultures and recombinant interleukin-1. In this study, deletion of the SAA1 promoter to -120 bp with respect to the transcriptional start site did not diminish promoter activity; however, deletion to -94 bp renders the promoter completely inactive. Functional analysis have demonstrated that a 66-bp DNA fragment spanning -138 bp to -73 bp could confer cytokine responsiveness to a heterologous thymidine kinase promoter. Within this 66-bp responsive element resided an NF kappa B-like-binding site and a C/EBP-like-binding site. Although each binding site alone could confer responsiveness when stimulated with conditioned media and TPA, the response was much weaker than that observed when both sites were present. Moreover, site-specific mutations of either binding site completely abolished SAA1 promoter activity. Taken together, these results suggest a functional importance for and cooperative interaction of these two nuclear-factor binding sites in the cytokine-induced expression of the rat SAA1 gene.
Zae Young Ryoo - One of the best experts on this subject based on the ideXlab platform.
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Serum Amyloid A1 is involved in Amyloid plaque aggregation and memory decline in Amyloid beta abundant condition
Transgenic Research, 2019Co-Authors: Soyoung Jang, Woo Young Jang, Minjee Choi, Wookbong Kwon, Junkoo Yi, Si Jun Park, Duhak Yoon, Zae Young RyooAbstract:Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment, progressive neurodegeneration, and Amyloid-β (Aβ) lesion. In the neuronal death and disease progression, inflammation is known to play an important role. Our previous study on acute-phase protein Serum Amyloid A1 (SAA1) overexpressed mice showed that the liver-derived SAA1 accumulated in the brain by crossing the brain blood barrier (BBB) and trigger the depressive-like behavior on mouse. Since SAA1 involved in immune responses in other diseases, we focused on the possibility that SAA1 may exacerbate the neuronal inflammation related to Alzheimer’s disease. A APP/SAA overexpressed double transgenic mouse was generated using Amyloid precursor protein overexpressed (APP)-c105 mice and SAA1 overexpressed mice to examine the function of SAA1 in Aβ abundant condition. Comparisons between APP and APP/SAA1 transgenic mice showed that SAA1 exacerbated Amyloid aggregation and glial activation; which lead to the memory decline. Behavior tests also supported this result. Overall, overexpression of SAA1 intensified the neuronal inflammation in Amyloid abundant condition and causes the greater memory decline compared to APP mice, which only expresses Aβ 1–42.
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Serum Amyloid A1 is involved in Amyloid plaque aggregation and memory decline in Amyloid beta abundant condition
Transgenic Research, 2019Co-Authors: Soyoung Jang, Woo Young Jang, Minjee Choi, Wookbong Kwon, Junkoo Yi, Si Jun Park, Duhak Yoon, Zae Young RyooAbstract:Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment, progressive neurodegeneration, and Amyloid-beta (Abeta) lesion. In the neuronal death and disease progression, inflammation is known to play an important role. Our previous study on acute-phase protein Serum Amyloid A1 (SAA1) overexpressed mice showed that the liver-derived SAA1 accumulated in the brain by crossing the brain blood barrier (BBB) and trigger the depressive-like behavior on mouse. Since SAA1 involved in immune responses in other diseases, we focused on the possibility that SAA1 may exacerbate the neuronal inflammation related to Alzheimer's disease. A APP/SAA overexpressed double transgenic mouse was generated using Amyloid precursor protein overexpressed (APP)-c105 mice and SAA1 overexpressed mice to examine the function of SAA1 in Abeta abundant condition. Comparisons between APP and APP/SAA1 transgenic mice showed that SAA1 exacerbated Amyloid aggregation and glial activation; which lead to the memory decline. Behavior tests also supported this result. Overall, overexpression of SAA1 intensified the neuronal inflammation in Amyloid abundant condition and causes the greater memory decline compared to APP mice, which only expresses Abeta 1-42.
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Serum Amyloid A1 levels and Amyloid deposition following a high fat diet challenge in transgenic mice overexpressing hepatic Serum Amyloid A1
Applied Physiology Nutrition and Metabolism, 2016Co-Authors: Woo Young Jang, Minjee Choi, Si Jun Park, Jain Jeong, Mincheol Kang, Yong Hun Sung, Zae Young RyooAbstract:Serum Amyloid A (SAA) is an acute-phase response protein in the liver, and SAA1 is the major precursor protein involved in Amyloid A Amyloidosis. This Amyloidosis has been reported as a complication in chronic inflammatory conditions such as arthritis, lupus, and Crohn's disease. Obesity is also associated with chronic, low-grade inflammation and sustained, elevated levels of SAA1. However, the contribution of elevated circulating SAA1 to metabolic disturbances and their complications is unclear. Furthermore, in several recent studies of transgenic (TG) mice overexpressing SAA1 that were fed a high-fat diet (HFD) for a relatively short period, no relationship was found between SAA1 up-regulation and metabolic disturbances. Therefore, we generated TG mice overexpressing SAA1 in the liver, challenged these mice with an HFD, and investigated the influence of elevated SAA1 levels. Sustained, elevated levels of SAA1 were correlated with metabolic parameters and local cytokine expression in the liver following 16 weeks on the HFD. Moreover, prolonged consumption (52 weeks) of the HFD was associated with impaired glucose tolerance and elevated SAA1 levels and resulted in systemic SAA1-derived Amyloid deposition in the kidney, liver, and spleen of TG mice. Thus, we concluded that elevated SAA1 levels under long-term HFD exposure result in extensive SAA1-derived Amyloid deposits, which may contribute to the complications associated with HFD-induced obesity and metabolic disorders.
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Serum Amyloid A1 levels and Amyloid deposition following a high-fat diet challenge in transgenic mice overexpressing hepatic Serum Amyloid A1.
Applied Physiology Nutrition and Metabolism, 2016Co-Authors: Woo Young Jang, Minjee Choi, Si Jun Park, Jain Jeong, Mincheol Kang, Yong Hun Sung, Zae Young RyooAbstract:Serum Amyloid A (SAA) is an acute-phase response protein in the liver, and SAA1 is the major precursor protein involved in Amyloid A Amyloidosis. This Amyloidosis has been reported as a complication in chronic inflammatory conditions such as arthritis, lupus, and Crohn’s disease. Obesity is also associated with chronic, low-grade inflammation and sustained, elevated levels of SAA1. However, the contribution of elevated circulating SAA1 to metabolic disturbances and their complications is unclear. Furthermore, in several recent studies of transgenic (TG) mice overexpressing SAA1 that were fed a high-fat diet (HFD) for a relatively short period, no relationship was found between SAA1 up-regulation and metabolic disturbances. Therefore, we generated TG mice overexpressing SAA1 in the liver, challenged these mice with an HFD, and investigated the influence of elevated SAA1 levels. Sustained, elevated levels of SAA1 were correlated with metabolic parameters and local cytokine expression in the liver following ...
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hepatic Serum Amyloid A1 aggravates t cell mediated hepatitis by inducing chemokines via toll like receptor 2 in mice
Journal of Biological Chemistry, 2015Co-Authors: Young Rae Ji, Zae Young RyooAbstract:Abstract Serum Amyloid A (SAA) is a pro-inflammatory molecule that induces leukocyte infiltration and promotes neutrophil adhesion to endothelial cells under inflammatory conditions. The aim of this study was to examine whether SaA1 aggravates T cell-mediated hepatitis by inducing chemokines in a liver specific SaA1 overexpressing transgenic (TG) mouse model. We generated TG mice in which SaA1 was overexpressed specifically in liver tissue. The chemokines monocyte chemotactic protein 1 (MCP1), MIP1α, MIP1β, interferon gamma-induced protein 10 (IP-10), and eotaxin were induced in SaA1 TG mice. After ConA treatment, SaA1 expression was higher in SaA1 TG mice than in wild-type (WT) mice. More severe liver injury, increased hepatocyte apoptosis, and higher levels of hepatic enzymes were observed in SaA1 TG mice than in WT mice. Liver infiltration of CD4+ T cells and macrophages increased after inducing hepatitis. Activation of T cells was higher in SaA1 TG mice than in WT mice and the populations of Th17 cells and regulatory T cells were altered by overexpressing SaA1 in TG mice. Secretion of various cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-6, increased in SaA1 TG mice. Injecting a Toll-like receptor 2 (TLR2) antagonist in vivo inhibited chemokine expression and IκBα phosphorylation and showed that the induction of chemokines by SaA1 was dependent on TLR2. Hepatic SaA1 accelerated T cell-mediated hepatitis by inducing chemokine production and activating T cells by TLR2. Thus, SaA1 might be a novel inflammatory factor that acts as a chemokine modulator in hepatitis.
M Osterland - One of the best experts on this subject based on the ideXlab platform.
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A link between inflammation and metastasis: Serum Amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4
Oncogene, 2015Co-Authors: M T Hansen, B Forst, Natascha Cremers, Luca Quagliata, Noona Ambartsumian, Birgitte Grum-schwensen, Jörg Klingelhöfer, A Abdul-al, Pia Herrmann, M OsterlandAbstract:S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins Serum Amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression.
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A link between inflammation and metastasis: Serum Amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4
Oncogene, 2014Co-Authors: M T Hansen, B Forst, Natascha Cremers, Luca Quagliata, Noona Ambartsumian, Birgitte Grum-schwensen, Jörg Klingelhöfer, A Abdul-al, Pia Herrmann, M OsterlandAbstract:A link between inflammation and metastasis: Serum Amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4
Hao Ying - One of the best experts on this subject based on the ideXlab platform.
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extracellular matrix remodeling effects of Serum Amyloid A1 in the human amnion implications for fetal membrane rupture
American Journal of Reproductive Immunology, 2018Co-Authors: Yawei Wang, Wangsheng Wang, Luyao Wang, Jiangwen Lu, Yi Lu, Chuyue Zhang, Wenjiao Li, Hao YingAbstract:PROBLEM: Rupture of fetal membranes is a crucial event at parturition, which is preceded by extensive extracellular matrix (ECM) remodeling. Our recent studies have demonstrated that the human fetal membranes are capable of de novo synthesis of Serum Amyloid A1 (SAA1), an acute phase protein, and the abundance of SAA1 in the amnion was increased at parturition. However, the exact role of SAA1 in human parturition remains to be established. METHOD OF STUDY: The effects of SAA1 on the abundance of collagenases and lysyl oxidase, the enzyme that cross-links collagens, were investigated in culture primary human amnion fibroblasts and tissue explants with an aim to examine the involvement of SAA1 in the ECM remodeling in the amnion. RESULTS: Serum Amyloid A1 (SAA1) time- and dose-dependently increased the abundance of collagenases MMP-1, MMP-8, and MMP-13, while decreased the abundance of lysyl oxidase-like 1 (LOXL1). These effects of SAA1 were attenuated by siRNA-mediated knockdown of the Toll-like receptor (TLR) 4 and its antagonist CLI-095, but not by siRNA-mediated knockdown of TLR2. Furthermore, the inhibitors for NF-κB (JSH-23) and mitogen-activated protein kinases (MAPKs) p38 (SB203580) and JNK (SP600125) could also attenuate the effects of SAA1, while the inhibitor for MAPK ERK1/2 (PD 98059) could block the effects of SAA1 only on MMP-1, MMP-8, and LOXL1 but not on MMP-13. CONCLUSION: These data highlight a possible role for SAA1 in ECM remodeling preceding membrane rupture by regulating the expression of collagenases MMP-1, MMP-8, MMP-13, and LOXL1 through TLR4-mediated activation of the NF-κB and MAPK pathways in amnion fibroblasts.
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Extracellular matrix remodeling effects of Serum Amyloid A1 in the human amnion: Implications for fetal membrane rupture.
American Journal of Reproductive Immunology, 2018Co-Authors: Yawei Wang, Wangsheng Wang, Luyao Wang, Jiangwen Lu, Yi Lu, Chuyue Zhang, Wenjiao Li, Hao YingAbstract:Rupture of fetal membranes is a crucial event at parturition, which is preceded by extensive extracellular matrix (ECM) remodeling. Our recent studies have demonstrated that the human fetal membranes are capable of de novo synthesis of Serum Amyloid A1 (SAA1), an acute phase protein, and the abundance of SAA1 in the amnion was increased at parturition. However, the exact role of SAA1 in human parturition remains to be established. The effects of SAA1 on the abundance of collagenases and lysyl oxidase, the enzyme that cross-links collagens, were investigated in culture primary human amnion fibroblasts and tissue explants with an aim to examine the involvement of SAA1 in the ECM remodeling in the amnion. Serum Amyloid A1 (SAA1) time- and dose-dependently increased the abundance of collagenases MMP-1, MMP-8, and MMP-13, while decreased the abundance of lysyl oxidase-like 1 (LOXL1). These effects of SAA1 were attenuated by siRNA-mediated knockdown of the Toll-like receptor (TLR) 4 and its antagonist CLI-095, but not by siRNA-mediated knockdown of TLR2. Furthermore, the inhibitors for NF-κB (JSH-23) and mitogen-activated protein kinases (MAPKs) p38 (SB203580) and JNK (SP600125) could also attenuate the effects of SAA1, while the inhibitor for MAPK ERK1/2 (PD 98059) could block the effects of SAA1 only on MMP-1, MMP-8, and LOXL1 but not on MMP-13. These data highlight a possible role for SAA1 in ECM remodeling preceding membrane rupture by regulating the expression of collagenases MMP-1, MMP-8, MMP-13, and LOXL1 through TLR4-mediated activation of the NF-κB and MAPK pathways in amnion fibroblasts. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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induction of pro inflammatory genes by Serum Amyloid A1 in human amnion fibroblasts
Scientific Reports, 2017Co-Authors: Wenjiao Li, Wangsheng Wang, Hao YingAbstract:Serum Amyloid A1 (SAA1) is an acute response protein, which is mainly produced by the liver, during infection. However, it remains unknown whether SAA1 can be produced in human fetal membranes where it is able to elicit events pertinent to labor initiation. We demonstrated that SAA1 was expressed in the fibroblasts and epithelium of the amnion and the trophoblasts of the chorion. Further study in human amnion fibroblasts showed that SAA1 production was augmented by interleukin-1β (IL-1β) and cortisol alone and synergistically, and SAA1 in turn induced the expression of IL-1β, interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and PGE2 production. These effects of SAA1 were mediated through activation of the NF-κB, p38 and ERK1/2 pathways via the toll-like receptor 4 (TLR4). Inhibition of TLR4 attenuated not only SAA1-induced activation of NF-κB, p38 and ERK1/2 but also increases in IL-1β, IL-6 and COX-2 expression. Moreover, SAA1 expression was increased in human amnion tissue following spontaneous labor. In conclusion, this study has demonstrated for the first time that SAA1 can be produced in human fetal membranes, which can be greatly induced in the presence of proinflammatory cytokines and glucocorticoids thereby producing effects associated with parturition.
Jin Ho Chung - One of the best experts on this subject based on the ideXlab platform.
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Serum Amyloid A1 secreted from uv irradiated keratinocytes induces matrix metalloproteinase 1 in fibroblasts through toll like receptor 4
Experimental Dermatology, 2016Co-Authors: Jang Hee Oh, Chi Hyun Park, Hyun Sun Yoon, Jin Ho ChungAbstract:Ultraviolet (UV) irradiation on skin triggers photoageing-related phenotypes such as formation of wrinkles. UV ray upregulates matrix metalloproteinase-1 (MMP-1), which in turn degrades extracellular matrix proteins, mostly collagens. Serum Amyloid A1 (SAA1) is an acute-phase protein of which plasma concentration increases in response to inflammation. Although the expression of SAA1 in the skin was reported, its function in the skin is yet to be studied. In this research, we found that the expression of SAA1 was increased in acute UV-irradiated buttock skin and photoaged forearm skin in vivo. UV irradiation also increased SAA1 in normal human epidermal keratinocytes (NHEK), and treatment of recombinant human SAA1 (rhSAA1) induced MMP-1 in normal human dermal fibroblasts (NHDF) but not in NHEK. Next, we demonstrated that NHDF treated with UV-irradiated keratinocyte-conditioned media showed the increased MMP-1 expression; however, this increase of MMP-1 in NHDF was inhibited by knockdown of SAA1 in NHEK. In addition, knockdown of Toll-like receptor 4 (TLR4) inhibited rhSAA1-induced MMP-1 expression in NHDF. Taken together, our data showed that UV-induced SAA1 production in NHEK, and this secreted SAA1 induced MMP-1 expression in NHDF in a paracrine manner through TLR4 signalling pathway. Therefore, our results suggest that SAA1 can be a potential mediator for UV-induced MMP-1 expression in human skin.
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Serum Amyloid A1 secreted from UV‐irradiated keratinocytes induces matrix metalloproteinase‐1 in fibroblasts through toll‐like receptor 4
Experimental Dermatology, 2016Co-Authors: Jang Hee Oh, Chi Hyun Park, Hyun Sun Yoon, Jin Ho ChungAbstract:Ultraviolet (UV) irradiation on skin triggers photoageing-related phenotypes such as formation of wrinkles. UV ray upregulates matrix metalloproteinase-1 (MMP-1), which in turn degrades extracellular matrix proteins, mostly collagens. Serum Amyloid A1 (SAA1) is an acute-phase protein of which plasma concentration increases in response to inflammation. Although the expression of SAA1 in the skin was reported, its function in the skin is yet to be studied. In this research, we found that the expression of SAA1 was increased in acute UV-irradiated buttock skin and photoaged forearm skin in vivo. UV irradiation also increased SAA1 in normal human epidermal keratinocytes (NHEK), and treatment of recombinant human SAA1 (rhSAA1) induced MMP-1 in normal human dermal fibroblasts (NHDF) but not in NHEK. Next, we demonstrated that NHDF treated with UV-irradiated keratinocyte-conditioned media showed the increased MMP-1 expression; however, this increase of MMP-1 in NHDF was inhibited by knockdown of SAA1 in NHEK. In addition, knockdown of Toll-like receptor 4 (TLR4) inhibited rhSAA1-induced MMP-1 expression in NHDF. Taken together, our data showed that UV-induced SAA1 production in NHEK, and this secreted SAA1 induced MMP-1 expression in NHDF in a paracrine manner through TLR4 signalling pathway. Therefore, our results suggest that SAA1 can be a potential mediator for UV-induced MMP-1 expression in human skin.
