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ABSTRACT: The five subunits of transcription factor NF-κB have distinct biological functions. NF-κB signaling is important for skin homeostasis and aging, but the contribution of individual subunits to normal skin biology and disease is unclear. Immunohistochemical analysis of the p50 and c-Rel subunits within lesional psoriatic and systemic sclerosis skin revealed abnormal epidermal expression patterns, compared with healthy skin, but RelA distribution was unaltered. The skin of Nfkb1(-/-) and c-Rel(-/-) mice is structurally normal, but epidermal thickness and proliferation are significantly reduced, compared with wild-type mice. We show that the primary defect in both Nfkb1(-/-) and c-Rel(-/-) mice is within keratinocytes that display reduced proliferation both in vitro and in vivo. However, both genotypes can respond to proliferative stress, with 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperproliferation and closure rates of full-thickness skin wounds being equivalent to those of wild-type controls. In a model of bleomycin-induced skin fibrosis, Nfkb1(-/-) and c-Rel(-/-) mice displayed opposite phenotypes, with c-Rel(-/-) mice being protected and Nfkb1(-/-) developing more fibrosis than wild-type mice. Taken together, our data reveal a role for p50 and c-Rel in regulating epidermal proliferation and homeostasis and a profibrogenic role for c-Rel in the skin, and identify a link between epidermal c-Rel expression and systemic sclerosis. Modulating the actions of these subunits could be beneficial for treating hyperproliferative or fibrogenic diseases of the skin.
American Journal Of Pathology 04/2013; · 4.89 Impact Factor
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ABSTRACT: BACKGROUND: Oxaliplatin-based chemotherapy has been linked to the development of sinusoidal obstruction syndrome (SOS), which is detrimental to outcome after liver resection for colorectal liver metastases (CLM). The aim of this study was to determine how the expression of genes involved in the transport and metabolism of FOLFOX chemotherapy impacts on tissue injury in a murine model of CLM. METHODS: Experimental CLM was established in C57/B16 mice and treated with FOLFOX chemotherapy. After 3 weeks, the animals were killed and RNA extracted from liver, spleen and tumour tissue. DNA damage was assessed by immunohistochemistry for γH2AX. Gene expression was determined by reverse transcriptase polymerase chain reaction. RESULTS: FOLFOX treatment was associated with an increase in the number of γH2AX-positive cells in both the spleen (P < 0.01) and tumour tissue (P < 0.01), but not the liver. Tissue resistance to injury following FOLFOX was associated with high expression of the copper transporter ATP7B. Differences in the expression of genes related to 5-fluorouracil metabolism or DNA repair did not correlate with the severity of tissue injury. CONCLUSIONS: High levels of expression of ATP7B are associated with resistance to tissue injury following FOLFOX chemotherapy. Polymorphisms in the ATP7B gene may explain varying susceptibility to SOS among patients following oxaliplatin-based chemotherapy.
HPB 12/2012; · 1.60 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: Wound healing is a normal physiological response to tissue injury which can occur in any organ. Mechanisms that orchestrate wound healing in different organs are surprisingly generic, involving generation of fibroblasts and myofibroblasts by differentiation processes that require extensive alterations in gene expression. This process and indeed phenotype of cells are orchestrated by the combined influences of molecular components of epigenome including DNA methylation, vast array of posttranslational modifications of the histone protein constituents of chromatin and regulatory noncoding RNAs of which microRNAs (miRs) are the most extensively studied. RECENT FINDINGS: Numerous studies from the last 12 months show all the three epigenetic mechanisms to be regulating generation and apoptosis of myofibroblasts in organs affected by perturbed wound healing. Furthermore, these mechanisms are involved in fibrotic disease itself, with some miRs and epigenetic drugs being tested for their therapeutic potential. SUMMARY: Fields of wound healing and fibrosis will be enriched over the next decade by plethora of new information regarding epigenetic control mechanisms which will hopefully provide new advances in diagnostics and prognostics. With the design of ever more specific epigenetic drugs, we may improve our ability to therapeutically optimize wound healing and prevent fibrosis in chronic disease and ageing.
Current opinion in rheumatology 10/2012; · 4.60 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) function as key regulators of liver fibrosis and are able to modulate the fibrogenic actions of non-parenchmal liver cells. The fibrogenic signalling events downstream of TLRs on Kupffer cells (KC) and hepatic stellate cells (HSC) are poorly defined. Here we describe the MAP3K Tumour Progression Locus-2 (Tpl2) as being important for the activation of ERK signalling in KC and HSC responding to stimulation of TLR4 and TLR9. KC lacking Tpl2 display defects with TLR induction of cytokines IL-1β, IL-10 and IL-23. Tpl2(-/-) HSC were unable to increase expression of fibrogenic genes IL-1β and TIMP-1, with the latter being due to defective stimulation of TIMP-1 promoter activity by TLRs. In order to determine the in vivo relevance of Tpl2 signalling in liver fibrosis we compared the fibrogenic responses of wild type and tpl2(-/-) mice in three distinct models of chronic liver injury. In the carbon tetrachloride and methionine-choline deficient diet models we observed a significant reduction in fibrosis in mice lacking Tpl2 compared with wild type controls. However, in the bile duct ligation model there was no impact of tpl2 deletion, which may reflect a lesser role for hepatic stellate cells in the wounding response to biliary injury. Conclusion: We conclude that Tpl2 is an important signal transducer for TLR activation of gene expression in KC and HSC via the ERK pathway and that suppression of its catalytic activity may be a route towards suppressing fibrosis caused by hepatocellular injuries. (HEPATOLOGY 2012.).
Hepatology 10/2012; · 11.66 Impact Factor
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ABSTRACT: The molecule serotonin (5-hydroxytryptamine or 5-HT) is involved in numerous biological processes both inside and outside of the central nervous system. 5-HT signals through 5-HT receptors and it is the diversity of these receptors and their subtypes that give rise to the varied physiological responses. It is clear that platelet derived serotonin is critical for normal wound healing in multiple organs including, liver, lung heart and skin. 5-HT stimulates both vasoconstriction and vasodilation, influences inflammatory responses and promotes formation of a temporary scar which acts as a scaffold for normal tissue to be restored. However, in situations of chronic injury or damage 5-HT signaling can have deleterious effects and promote aberrant wound healing resulting in tissue fibrosis and impaired organ regeneration. This review highlights the diverse actions of serotonin signaling in the pathogenesis of fibrotic disease and explores how modulating the activity of specific 5-HT receptors, in particular the 5-HT2 subclass could have the potential to limit fibrosis and restore tissue regeneration. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
Biochimica et Biophysica Acta 09/2012; · 4.66 Impact Factor
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Anna Moles,
Ana M Sanchez,
Paul S Banks,
Lindsay B Murphy,
Saimir Luli,
Lee Borthwick,
Andrew Fisher,
Steven O'Reilly,
Jacob M van Laar,
Steven A White,
Neil D Perkins,
Alastair D Burt, Derek A Mann,
Fiona Oakley
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ABSTRACT: Phosphorylation of the RelA subunit at serine 536 (RelA-P-Ser(536) ) is important for hepatic myofibroblast survival and is mechanistically implicated in liver fibrosis. Here we show that a cell permeable competing peptide, P6 functions as a specific targeted inhibitor of RelA-P-Ser(536) in vivo and exerts an anti-fibrogenic effect in two progressive liver disease models but does not impair hepatic inflammation or innate immune responses after LPS challenge. Using kinase assays and western blot we confirm that P6 is a substrate for the inhibitory kappa B Kinases (IKK) IKKα and IKKβ and in human hepatic myofibroblasts P6 prevents RelA-P-Ser(536) but does not affect IKK activation of IκBα. We demonstrate that RelA-P-Ser(536) is a feature of human lung and skin fibroblasts but not lung epithelial cells in vitro and is present in sclerotic skin and the diseased lungs of patients suffering from idiopathic pulmonary fibrosis. RelA-P-Ser(536) may therefore be a core fibrogenic regulator of fibroblast phenotype. (HEPATOLOGY 2012.).
Hepatology 09/2012; · 11.66 Impact Factor
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Müjdat Zeybel,
Timothy Hardy,
Yi K Wong,
John C Mathers,
Christopher R Fox,
Agata Gackowska,
Fiona Oakley,
Alastair D Burt,
Caroline L Wilson,
Quentin M Anstee,
Matt J Barter,
Steven Masson,
Ahmed M Elsharkawy, Derek A Mann,
Jelena Mann
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ABSTRACT: We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F(1) and F(2) generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.
Nature medicine 09/2012; · 27.14 Impact Factor
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Journal of Hepatology 07/2012; · 9.26 Impact Factor
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ABSTRACT: Therapies to limit or reverse fibrosis have proven unsuccessful, highlighting the need for a greater understanding of basic mechanisms that drive fibrosis and, in particular, the link between fibrosis and inflammation. It has been shown that pro-fibrotic transforming growth factor β1 (TGF-β1)-driven epithelial-to-mesenchymal transition (EMT) can be accentuated by tumor necrosis factor α (TNF-α). TGF-β-activated kinase 1 (TAK1) is activated by both TGF-β1 and TNF-α, activating both nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling pathways. In this study, we evaluated the potential for TAK1 to modulate the synergistic effect between TGF-β1 and TNF-α in driving EMT. Co-stimulation with TGF-β1 and TNF-α induced an accentuated and extended phosphorylation of TAK1 compared to either alone. TAK1 signaled downstream via nuclear factor kappa-light-chain-enhancer of activated B cells, and Jun N-terminal kinase-2, but independent of Jun N-terminal kinase-1, extracellular signal-regulated kinase-1/2, or p38 mitogen-activated protein kinase signaling to drive EMT in bronchial epithelial cells. Blocking either TAK1 or Jun N-terminal kinase-2 inhibited EMT. TAK1 phosphorylation was increased in the airway epithelium of patients with fibrotic airway disease. These data identify factors leading to and affected by accentuated and extended TAK1 phosphorylations potential novel therapeutic targets in inflammation-driven fibrotic diseases.
American Journal Of Pathology 04/2012; 180(6):2293-308. · 4.89 Impact Factor
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Maria Jesus Perugorria,
Caroline L Wilson,
Mujdat Zeybel,
Meagan Walsh,
Shilu Amin,
Stuart Robinson,
Steven A White,
Alastair D Burt,
Fiona Oakley,
Hidekazu Tsukamoto, Derek A Mann,
Jelena Mann
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ABSTRACT: Transdifferentiation of hepatic stellate cells (HSCs) to a myofibroblast-like phenotype is the pivotal event in liver fibrosis. The dramatic change in phenotype associated with transdifferentiation is underpinned by a global change in gene expression. Orchestrated changes in gene expression take place at the level of chromatin packaging which is regulated by enzymatic activity of epigenetic regulators that in turn affect histone modifications. Using expression profiling of epigenetic regulators in quiescent and activated primary HSCs we found a number of histone methyltransferases including MLL1, MLL5, Set1 and ASH1 to be highly up-regulated during transdifferentiation of HSCs. All of these histone methyltransferases regulate methylation of lysine 4 of histone H3, which is a signature of actively transcribed genes. We therefore postulated that one or more of these enzymes may be involved in positively influencing expression of profibrogenic genes. CONCLUSION: We find that ASH1 directly binds to the regulatory regions of alpha smooth muscle actin (αSMA), collagen I, tissue inhibitor of metalloproteinase-1 (TIMP1) and transforming growth factor beta1 (TGFβ1) in activated HSCs while depletion of ASH1 caused broad suppression of fibrogenic gene expression. We also discovered that MeCP2 positively regulates ASH1 expression and therefore identify ASH1 as a key transcriptional activator component of the MeCP2 epigenetic relay pathway that orchestrates coordinated induction of multiple profibrogenic genes.
Hepatology 04/2012; 56(3):1129-39. · 11.66 Impact Factor
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ABSTRACT: Fibrosis is a common pathological process for the majority of liver diseases which in a significant minority of patients leads to end-stage cirrhosis and/or hepatocellular carcinoma. Data emerging from small rodent models of chronic liver disease have demonstrated that fibrotic extracellular matrix can be remodelled and near-normal hepatic architecture regenerated upon cessation of injury. Moreover, regression of liver fibrosis in these model systems can be stimulated with drugs that target the activities of fibrogenic hepatic stellate cells. These findings are exciting as they suggest that established fibrosis is susceptible to regression and possibly even reversion. Alongside these experimental studies is a growing body of clinical data that suggest regression of fibrosis may also occur in liver disease patients for whom an effective treatment is available for their underlying liver injury. This paper provides an up-to-date review of the currently available clinical data and also considers technical caveats that highlight the need for caution in establishing a new dogma that human liver fibrosis is reversible.
Journal of Hepatology 01/2012; 56(5):1171-80. · 9.26 Impact Factor
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Silvia Gaspar-Pereira,
Nicola Fullard,
Paul A Townsend,
Paul S Banks,
Elizabeth L Ellis,
Christopher Fox,
Aidan G Maxwell,
Lindsay B Murphy,
Adam Kirk,
Ralf Bauer,
Jorge H Caamaño,
Nichola Figg,
Roger S Foo,
Jelena Mann, Derek A Mann,
Fiona Oakley
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ABSTRACT: Cardiac remodeling and hypertrophy are the pathological consequences of cardiovascular disease and are correlated with its associated mortality. Activity of the transcription factor NF-κB is increased in the diseased heart; however, our present understanding of how the individual subunits contribute to cardiovascular disease is limited. We assign a new role for the c-Rel subunit as a stimulator of cardiac hypertrophy and fibrosis. We discovered that c-Rel-deficient mice have smaller hearts at birth, as well as during adulthood, and are protected from developing cardiac hypertrophy and fibrosis after chronic angiotensin infusion. Results of both gene expression and cross-linked chromatin immunoprecipitation assay analyses identified transcriptional activators of hypertrophy, myocyte enhancer family, Gata4, and Tbx proteins as Rel gene targets. We suggest that the p50 subunit could limit the prohypertrophic actions of c-Rel in the normal heart, because p50 overexpression in H9c2 cells repressed c-Rel levels and the absence of cardiac p50 was associated with increases in both c-Rel levels and cardiac hypertrophy. We report for the first time that c-Rel is highly expressed and confined to the nuclei of diseased adult human hearts but is restricted to the cytoplasm of normal cardiac tissues. We conclude that c-Rel-dependent signaling is critical for both cardiac remodeling and hypertrophy. Targeting its activities could offer a novel therapeutic strategy to limit the effects of cardiac disease.
American Journal Of Pathology 12/2011; 180(3):929-39. · 4.89 Impact Factor
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ABSTRACT: Hepatic stellate cells (HSCs) undergo myofibroblastic transdifferentiation (activation) to participate in liver fibrosis and identification of molecular targets for this cell fate regulation is essential for development of efficacious therapeutic modalities for the disease. Peroxisomal proliferator-activated receptor γ (PPARγ) is required for differentiation of HSCs and its epigenetic repression underlies HSC activation. The herbal prescription Yang-Gan-Wan (YGW) prevents liver fibrosis, but its active ingredients and molecular mechanisms are unknown. Here we demonstrate YGW prevents and reverses HSC activation by way of epigenetic derepression of Pparγ involving reductions in MeCP2 expression and its recruitment to Pparγ promoter, suppressed expression of PRC2 methyltransferase EZH2, and consequent reduction of H2K27di-methylation at the 3' exon. High-performance liquid chromatography / mass spectrometry (HPLC/MS) and nuclear magnetic resonance (NMR) analyses identify polyphenolic rosmarinic acid (RA) and baicalin (BC) as active phytocompounds. RA and BC suppress the expression and signaling by canonical Wnts, which are implicated in the aforementioned Pparγ epigenetic repression. RA treatment in mice with existing cholestatic liver fibrosis inhibits HSC activation and progression of liver fibrosis. Conclusion: These results demonstrate a therapeutic potential of YGW and its active component RA and BC for liver fibrosis by way of Pparγ derepression mediated by suppression of canonical Wnt signaling in HSCs.
Hepatology 11/2011; 55(4):1271-81. · 11.66 Impact Factor
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ABSTRACT: Epithelial to mesenchymal transition (EMT) is a process by which an epithelial cell alters its phenotype to that of a mesenchymal cell and plays a critical role in embryonic development, tumour invasion and metastasis and tissue fibrosis. Transforming growth factor-β1 (TGF-β1) continues to be regarded as the key growth factor involved in driving EMT however recently tumour necrosis factor α (TNFα) has been demonstrated to accentuate TGF-β1 driven EMT. In this study we investigate how various signalling pathways contribute to this accentuated effect. A549 cells were treated with TGF-β1 (10 ng/ml), TNFα (20 ng/ml) or a combination of both for 72 h and EMT assessed. The effect of selective inhibition of the SMAD, MAPK and NF-κB pathways on EMT was assessed. A549 cells treated with TGF-β1 downregulate the expression of epithelial markers, increase the expression of mesenchymal markers, secrete matrix-metalloproteinases and become invasive. Significantly, TGF-β1 driven EMT is accentuated by co-treatment with TNFα. SMAD 3 inhibition attenuated TGF-β1 driven EMT but has no effect on the accentuation effect of TNFα. However, inhibiting IKKβ blocked both TGF-β1 driven EMT and the accentuating action of TNFα. Inhibiting p38 and ERK signalling had no effect on EMT. TNFα accentuates TGF-β1 driven EMT in A549 cells via a SMAD 2/3 independent mechanism involving the NF-κB pathway independent of p38 and ERK 1/2 activation.
Cancer Microenvironment 07/2011; 5(1):45-57.
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ABSTRACT: Research in the past three decades has identified key mediators and signaling mechanisms responsible for myofibroblastic transdifferentiation (MTD) of hepatic stellate cells (HSC), the pivotal event in liver fibrogenesis. Yet, fundamental understanding of the MTD from the viewpoint of cell fate or lineage regulation has been elusive. Recent studies using genetic cell fate mapping techniques demonstrate HSC are derived from mesoderm and at least in part via septum transversum and mesothelium. HSC express markers for different cell types derived from multipotent mesenchymal progenitors. A regulatory commonality between differentiation of adipocytes and that of HSC is shown, and a shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central to this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor-γ (PPAR-γ). Restored expression of PPAR-γ and/or other adipogenic transcription factors reverses myofibroblastic HSC to differentiated cells. In MTD, Pparγ is epigenetically repressed by induction of methyl-CpG binding protein 2 and its enrichment to the promoter and polycomb repressive complex-facilitated histone H3 lysine 27 di/tri-methylation at the 3' exons. Blocking canonical wingless-related MMTV integration site (Wnt) signaling in myofibroblastic HSC with the co-receptor antagonist Dickkopf-1, abrogates these epigenetic mechanisms, restores PPAR-γ expression and HSC differentiation. Necdin, a melanoma antigen family protein, is identified as an upstream mediator for induction of the canonical Wnt10b and consequent Pparγ repression and HSC MTD. The identified morphogen-induced epigenetic regulation of Pparγ and HSC fate may serve as a novel target for manipulation of liver fibrosis and mesenchymal-epithelial interactions in liver regeneration.
Hepatology Research 04/2011; 41(7):675-82. · 2.20 Impact Factor
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Mohammad R Ebrahimkhani,
Fiona Oakley,
Lindsay B Murphy,
Jelena Mann,
Anna Moles,
Maria J Perugorria,
Elizabeth Ellis,
Anne F Lakey,
Alastair D Burt,
Angela Douglass,
Matthew C Wright,
Steven A White,
Fabrice Jaffré,
Luc Maroteaux, Derek A Mann
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ABSTRACT: Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.
Nature medicine 01/2011; 17(12):1668-73. · 27.14 Impact Factor
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ABSTRACT: The pro-inflammatory functions of NF-kappaB must be tightly regulated to prevent inappropriate tissue damage and remodelling caused by activated inflammatory and wound-healing cells. The p50 subunit of NF-kappaB is emerging as an important repressor of immune and inflammatory responses, but by mechanisms that are poorly defined. This study aims to delineate p50 target genes in activated hepatic stellate cells and to outline mechanisms utilised in their repression.
Hepatic stellate cells were isolated from nfkb1(p50)-deficient or Wt mice and gene expression compared using microarray. Target genes were verified by qRT-PCR and p50-mediated HDAC-1 recruitment to the target genes demonstrated using chromatin immunoprecipitation.
We identify p50 as transcriptional repressor of multiple pro-inflammatory genes including Ccl2, Cxcl10, Gm-csf, and Mmp-13. These genes are over-expressed in nfkb1(p50)-deficient mice suffering from chronic hepatitis and in fibrogenic/inflammatory hepatic stellate cells isolated from nfkb1(-/-) liver. We identify Mmp-13 as a bona-fide target gene for p50 and demonstrate that p50 is required for recruitment of the transcriptional repressor histone deacetylase (HDAC)-1 to kappaB sites in the Mmp-13 promoter. Chromatin immunoprecipitations identified binding of HDAC-1 to specific regulatory regions of the Ccl2, Cxcl10, Gm-csf genes that contain predicted kappaB binding motifs. Recruitment of HDAC-1 to these genes was not observed in nfkb1(-/-) cells suggesting a requirement for p50 in a manner similar to that described for Mmp-13.
Recruitment of HDAC-1 to inflammatory genes provides a widespread mechanism to explain the immunosuppressive properties of p50.
Journal of Hepatology 09/2010; 53(3):519-27. · 9.26 Impact Factor
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ABSTRACT: To determine whether genetic variation within genes integral to the Toll-like receptor (TLR) and NFkappaB signalling systems, two cardinal regulators of inflammatory and immune responses, contributes towards the observed variation in response to tumour necrosis factor (TNF) blocking agents in patients with rheumatoid arthritis (RA).
Pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 24 candidate genes were selected and genotyped in a large UK cohort of patients receiving anti-TNF therapy for RA. Multivariate regression analyses were performed to test association between individual genotypes, under an additive model, and treatment response at 6 months' follow-up assessed using both the absolute change in 28-joint count Disease Activity Score (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Analyses were performed across subgroups comprising etanercept-, infliximab- and infliximab/adalimumab-treated patients as well as the combined anti-TNF-treated cohort. p Values <0.05 were considered statistically significant.
A total of 187 SNPs were successfully genotyped and analysed in 909 patients. Eight SNPs spanning six genes demonstrated nominal evidence of association with response (DAS28) across the anti-TNF-treated subgroups, six of which were restricted to etanercept-treated patients. Twelve SNPs spanning nine genes demonstrated nominal evidence of association with treatment response (DAS28 and/or EULAR) across the combined anti-TNF cohort. These included SNPs mapping to MyD88 (rs7744) and CHUK (rs11591741), which were associated under each model applied (etanercept-treated and combined anti-TNF cohort analysis (DAS28 and EULAR)).
Several SNPs mapping to the TLR and NFkappaB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.
Annals of the rheumatic diseases 07/2010; 69(7):1315-20. · 8.11 Impact Factor
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Journal of Hepatology 06/2010; 52(6):949-50. · 9.26 Impact Factor
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Karen Wallace,
David E Cowie,
Dimitrios K Konstantinou,
Stephen J Hill,
Torunn E Tjelle,
Andrew Axon,
Matthew Koruth,
Steven A White,
Harald Carlsen, Derek A Mann,
Matthew C Wright
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ABSTRACT: PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A - which more effectively prevents PBC recurrence in transplanted patients than FK506 - is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract inflammatory cell recruitment), feeding a PXR activator inhibited inflammation, TNFalpha and Il-1alpha mRNA expression in SJL/J-PXR(+/+), but not SJL/J-PXR(-/-). Monocytic cells - a major source of inflammatory mediators such as TNFalpha - expressed the PXR and PXR activators inhibited endotoxin-induced NF-kappaB activation and TNFalpha expression. PXR activation also inhibited endotoxin-stimulated TNFalpha secretion from liver monocytes/macrophages isolated from PXR(+/+) mice, but not from cells isolated from PXR(-/-) mice. To confirm that PXR activation inhibits NF-kappaB in vivo, 3x-kappaB-luc fibrotic mice (which express a luciferase gene regulated by NF-kappaB) were imaged after treatment with the hepatotoxin CCl(4). PXR activator inhibited the induction of hepatic NF-kappaB activity without affecting CCl(4) toxicity/hepatic damage. Using a PXR reporter gene assay, cyclosporin A - but not FK506 - was shown to be a direct PXR activator, and also to induce expression of the classic PXR-regulated CYP3A4 gene in human hepatocytes and in a cell line null for the FXR, a nuclear receptor with similar properties to the PXR. CONCLUSION: PXR activation is anti-inflammatory in the liver and the effects of cyclosporin A in PBC disease recurrence may be mediated in part via the PXR. Since PXR activation promotes hepatocyte growth and is also anti-fibrogenic, the PXR may be an excellent drug target for the treatment of chronic inflammatory liver disease.
The Journal of steroid biochemistry and molecular biology 04/2010; 120(2-3):137-48. · 2.66 Impact Factor
