Preface - Ous-research.no

Role of the Liver X receptors (LXRs) in inflammatory modulation
Principal investigator:
Joanna Ågren, MD, PhD student (OUH/UiO)
Supervisors
Maria K. Dahle, PhD (UiO)
Michael R. Daws, PhD (UiO)
Håvard Attramadal, Professor, MD, PhD (OUH/UiO)
Research area
Sepsis is a clinical syndrome where an infection (e.g. pneumonia or urinary tract infection)
causes systemic illness. Delayed initiation of treatment may lead to organ failure (severe
sepsis) and/or septic shock. Severe sepsis has an overall incidence of 2.8/1000 population
and a mortality rate of 30%. It is believed that sepsis, and the following organ injury, develops
when the body’s own regulation of the inflammatory responses to an infection is out
of control and defense mechanisms overshoot, rather than from the infectious agent alone.
Thus, the complex pathogenesis of sepsis involves several factors, including dysregulation
of the immune and endocrine systems, disseminated intravascular coagulation (DIC), genetic
susceptibility, and derangement of energy metabolism.
Aims
Our major aim is to study factors that may modulate the overshooting inflammatory responses in sepsis and promote a better balanced
immune defense. We believe that the liver X receptor (LXR) may have such properties and intend to elucidate the potential of LXR
as an inflammatory modulator in sepsis.
Liver X Receptor and Inflammation
Liver X receptor (LXR) is a ligand binding transcription factor and belong to the family of nuclear hormone receptors. The two subtypes
of LXR, LXRα and LXRβ, sense intracellular metabolites of cholesterol and are important regulators of cholesterol, fatty acid and
glucose metabolism. Studies have also indicated that the LXRs are involved in regulation of both acute and chronic inflammation. We
have previously demonstrated that activation of LXR by a synthetic agonist (GW3965) reduces liver injury and modulates systemic
inflammation in rats subjected to acute endotoxemia or polymicrobial sepsis, and that liver injury is increased in LXR-deficient mice in
the same models. Our in vitro studies have also shown that the release of pro-inflammatory mediators from white blood cells (Kupffer
cells (liver macrophages) and human monocytes) is reduced when the cells are pretreated with the synthetic LXR agonist before
stimulation with the gram negative cell wall component lipopolysaccharide (LPS).
To study the impact of LXR on inflammation, we use models that closely resembles the endogenous responses during an infection. For
example, we use a model of human whole blood as well as cultures of freshly isolated human white blood cells (monocytes, macrophages,
neutrophils and T cells). We also use murine models to study the systemic effect of LXR on inflammation. The cecal ligation
and puncture model resembles acute polymicrobial sepsis, and the oil induced arthritis model is used to study immune responses in
chronic inflammatory disease.
In 2010, the focus has mainly been on the different subtypes of LXR and their individual impact on inflammatory responses. In particular,
we have studied cytokine responses and markers of macrophage polarization and apoptosis following CLP in organs from mice
deficient in either LXRα or LXRβ. In parallel, we have studied the effects of LXRα or LXRβ knockdown by siRNA on cytokine responses
in human macrophages. Furthermore, at the immunobiological laboratory at the Department of Anatomy, Institute of Basic Medical
Sciences, UiO, we have studied the effect of LXR activation on the development of oil induced arthritis and on the migration of dendritic
cells to lymph nodes in this model.
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