PROGRAMM JAHRESTAGUNG 2012 30. Nov. – 2. Dez ... - ÖGDV

Poster Allergologie und Immunologie
P 8
Pregnane X Receptor (PXR) modulates CCR7 and Langerhans cell migration via
TGF-beta1.
Sandrine Dubrac 1
Andreas Elentner 1
Martin Hermann 2
Frank Gonzalez 3
Matthias Schmuth 1
1 Department of Dermatology Innsbruck Medical University A-6020-Innsbruck Austria.
2 KTM-ZIT Laboratory, Department of General and Transplant Surgery, Innsbruck
Medical University, Innsbruck, 6020, Austria.
3 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland USA
Introduction: The pregnane X receptor (PXR) is a member of the nuclear receptor
superfamily that regulates the transcription of genes involved in all phases of
endo- and xeno-biotic metabolism and thus prevents toxic accumulation of metabolites
within cells. PXR expression was found primarily in the gastro-intestinal tract and liver
and lately in cells from the immune system such as T and B lymphocytes in both human
and mouse.
Methods and Results: PXR is expressed in different subsets of mouse and human
immature DC especially Langerhans cells (LC) and is down-regulated in mature DC. PXR
activation down-regulates CCR7 expression at the cell surface of mouse LC without
affecting expression of other maturation markers such as CD40, CD86 and CXCR4 in
vitro. In contrast, PXR antagonism by A-792611 up-regulates expression of CCR7 on LC.
In vivo, PXR deficiency increases while transgenic expression of PXR decreases LC
emigration from epidermis. Interestingly, Langerin+ cells lose PXR while migrating into
skin tumors and PXR expression is lowered in intra-tumoral CCR7+ cells in mice.
Furthermore, PXR activation increases expression of TGF-beta1 and SOCS-1 in epidermal
cells while PXR antagonism has opposite effects. Time course of TGF-beta1 and SOCS-1
expression shows an early up-regulation of TGF-beta1 (T2 hrs) and SOCS-1 (T4 hrs) after
PXR activation in epidermal cells. Neutralization of TGF-beta1 in epidermal cells reverses
effects of PXR activation on CCR7 expression at the cell surface of LC in contrast to SOCS-1
silencing. All together these results demonstrate that PXR controls CCR7 and LC
migration via TGF-beta1.
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