Maria K Dahle

Publications (29) View all

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  Available from: Maria K Dahle

  Article: 9-cis retinoic acid inhibits inflammatory responses of adherent monocytes and increases their ability to induce classical monocyte migration.

  Ingrid B M Kolseth, Joanna Agren, Vibeke Sundvold-Gjerstad, Staale P Lyngstadaas, Jacob E Wang, Maria K Dahle
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  ABSTRACT: Patients with vitamin A/retinol deficiency are shown to be prone to infections and to suffer from increased inflammation, effects which can be remedied by vitamin A supplements. We aimed to study how human monocytes from the peripheral venous blood of healthy donors acted within the initial hours after adherence and exposure to bacterial endotoxin in the presence or absence of the 9-cis-isomer of retinoic acid (9cisRA). We found that adherent human monocytes were dominated by the CD14dimCD16+ subtype. Pretreatment with 9cisRA for 1 h significantly decreased lipopolysaccharide (LPS)-induced mRNA expression and protein release of tumor necrosis factor (TNF)α, interleukin (IL)-6 and chemokine ligands (CCL)3 and CCL4. In contrast, treatment with 9cisRA rapidly enhanced the production of monocyte chemoattractive protein/CCL2. 9cisRA treatment also led to enhanced migration of classical CD14high monocytes in a transwell in vitro system. We conclude that 9cisRA treatment of human adherent monocytes attenuates the inflammatory responses to LPS and induces the attraction of classical monocytes, a feature which may help explain why supplements administered to vitamin A-deficient patients counteract inflammation and increases the ability to fight infections.
  Journal of Innate Immunity 12/2011; 4(2):176-86. · 4.21 Impact Factor
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  Article: Liver X receptor protects against liver injury in sepsis caused by rodent cecal ligation and puncture.

  Yun Yong Wang, Una Ryg, Maria K Dahle, Knut R Steffensen, Christoph Thiemermann, Irshad H Chaudry, Finn P Reinholt, Jon L Collins, Hilde I Nebb, Ansgar O Aasen, Jan-Åke Gustafsson, Jacob E Wang
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  ABSTRACT: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP). Rats were subjected to CLP sepsis or a sham operation. Some were treated with the synthetic LXR agonist GW3965 0.3 mg/kg 30 min prior to the CLP procedure, and organs and plasma were harvested at 3, 10, 18, or 24 h. Organs were analyzed for RNA expression by quantitative polymerase chain reaction or for morphologic differences by histologic review. Organ injury and inflammatory markers were measured in plasma. Results: Expression of the LXRα gene was decreased in the livers of CLP rats compared with sham-operated rats. Administration of a synthetic agonist of LXR (GW3965) reduced biochemical indices of liver injury in the blood of CLP rats. We also demonstrated that liver injury associated with CLP is aggravated in LXRα- and LXRαβ-deficient mice compared with wild-type and LXRβ-deficient mice, indicating a role for LXRα in protecting the liver. The enhanced liver injury in LXR-deficient mice was associated with elevated plasma concentrations of high mobility group box 1, a late mediator of inflammation and a known factor in the pathology of this model. Collectively, these results argue in favor of a role for LXRα in protection against liver injury in experimental sepsis induced by CLP.
  Surgical Infections 08/2011; 12(4):283-9. · 1.80 Impact Factor
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  Available from: Maria K Dahle

  Article: Cecal ligation and puncture sepsis is associated with attenuated expression of adenylyl cyclase 9 and increased miR142-3p.

  Petter K Risøe, Una Ryg, Yun Yong Wang, Arkady Rutkovskiy, Bård Smedsrød, Guro Valen, Maria K Dahle
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  ABSTRACT: The host inflammatory response in sepsis may be resolved by endogenous anti-inflammatory immune cell responses, avoiding fatal pathogenesis, organ injury, and death. The intracellular signaling mediator cyclic 3'5'-adenosine monophosphate is a potent modulator of inflammatory responses and initiates the polarization of immune cells in a direction that suppresses inflammatory activation. Cyclic 3'5'-adenosine monophosphate is enzymatically produced by adenylyl cyclases (ACs). The expression of ACs is previously shown to be reduced in rat organs after in vivo endotoxemia, concurrent with the progressing systemic inflammation. In the present study, tissue AC gene expression and regulation are explored in a rat model of cecal ligation and puncture (CLP) sepsis. Eighteen hours after CLP operation, expression of several AC isoforms in the liver, spleen, and kidney was reduced, significantly so for AC9 in all tissues. AC9 expression is regulated by the microRNA miR142-3p in T cells. When microRNA was extracted and amplified for miR142-3p expression, it was increasingly expressed 18 h after CLP. A correlation between increased miR142-3p and decreased AC9 expression was found in the liver, kidney, and spleen, and when hepatocytes, Kupffer cells (KCs), and liver sinusoidal endothelial cells were isolated after CLP, reduced AC expression and increased miR142-3p expression were found in KCs and liver sinusoidal endothelial cells. Transfecting a miR142-3p inhibitor probe in rat KCs abolished LPS-mediated AC9 inhibition in vitro. These results indicate that CLP leads to miR142-3p-mediated AC9 reduction in liver macrophages, which may further limit cyclic 3'5'-adenosine monophosphate signaling and the ability of macrophages to resolve the proinflammatory response.
  Shock (Augusta, Ga.) 06/2011; 36(4):390-5. · 2.87 Impact Factor
• Article: The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro.

  H Scholz, T Lund, M K Dahle, J L Collins, O Korsgren, J E Wang, A Foss
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  ABSTRACT: Optimising islet culture conditions may be one strategy for reducing islet loss prior to, and immediately after, islet transplantation. Liver X receptor (LXR) agonism has previously been shown to increase insulin release from pancreatic islets and reduce inflammation in leucocytes. Our aim was to investigate whether the synthetic LXR agonist GW3965 could modulate the inflammatory status of human pancreatic islets. Levels of pro-inflammatory cytokines and tissue factor in isolated human islets were determined by TaqMan low density array and/or real-time quantitative RT-PCR (mRNA levels) and enzyme immunoassay (EIA) (protein levels). Islet viability was measured using intracellular ATP content, ADP/ATP ratio, mitochondrial dehydrogenase activity (XTT assay) and insulin secretion in a dynamic glucose-challenge model. Apoptosis was determined by EIA measurement of histone-DNA complexes present in cytoplasm and by assaying caspase-3/-7 activity. Treatment of LPS-stimulated human islets with the synthetic LXR agonist GW3965 (1 micromol/l) for 24 h reduced mRNA and protein levels of selected pro-inflammatory cytokines (IL-8, monocyte chemotactic protein-1 and tissue factor). Moreover, GW3965 had no adverse effect on insulin secretion, islet viability or apoptosis. No excess of lipid accumulation could be detected with the dosage and exposure time used. LXR activation suppresses inflammation in human islets in vitro without adverse effects on islet viability. Short-term moderate activation of LXR prior to islet transplantation may represent a possible strategy for improving post-transplant islet survival.
  Diabetologia 06/2009; 52(7):1352-62. · 6.81 Impact Factor
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  Available from: Maria K Dahle

  Article: Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages.

  Yun Yong Wang, Maria K Dahle, Knut R Steffensen, Finn P Reinholt, Jon L Collins, Christoph Thiemermann, Ansgar O Aasen, Jan-Ake Gustafsson, Jacob E Wang
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  ABSTRACT: Modulation of the host inflammatory response to infection may be a key approach to improve the outcome of patients with sepsis and organ injury. We previously reported that pretreatment of rats with the liver X receptor (LXR) agonist GW3965 reduced the liver injury associated with endotoxemia and attenuated the production of TNF-alpha by rat Kupffer cells. Here, we examine the dose-dependent effect of GW3965 on liver injury and cytokine production in a rat model of endotoxemia and explore the mechanisms underlying TNF-alpha attenuation in Kupffer cells. Low doses of GW3965 (0.1 or 0.3 mg/kg) administered 30 min before infusion of LPS and peptidoglycan significantly attenuated the increase in plasma levels of the liver injury markers alanine aminotransferase and bilirubin (6 h) as well as the inflammatory mediators TNF-alpha (1 h) and prostaglandin E2 (6 h) associated with endotoxemia. In contrast, pretreatment with a higher dose of GW3965 (1.0 mg/kg) had no such effect. Studies in primary cultures of rat Kupffer cells demonstrated that LXR agonist treatment attenuated both the secreted and cell-associated levels of TNF-alpha, whereas TNF-alpha mRNA levels were not altered. Phosphorylated p38 mitogen-activated protein kinase, which plays a major role in production of TNF-alpha at the posttranscriptional level, was attenuated by GW3965 treatment in Kupffer cells. Experiments in murine LXR-deficient Kupffer cells demonstrated enhanced production of TNF-alpha in Kupffer cells from LXR-alpha(-/-) mice when challenged with LPS compared with LXR-beta(-/-) and wild-type Kupffer cells. Taken together, these results argue in favor of a novel mechanism for LXR-mediated attenuation of liver injury by interfering with posttranscriptional regulation of TNF-alpha in Kupffer cells.
  Shock (Augusta, Ga.) 04/2009; 32(5):548-53. · 2.87 Impact Factor