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Abstract Number: 1500

Activation of Pregnane X Receptor Induces Regression of Experimental Dermal Fibrosis

Christian Beyer1, Alla Skapenko2, Alfiya Distler3, Clara Dees4, Helena Reichert5, Louis E. Munoz3, Jan Leipe6, Hendrik Schulze-Koops7, Oliver Distler8, Georg Schett9 and Joerg HW Distler3, 1Department of Internal Medicine 3, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 2Division of Rheumatology and Clinical Immunology, Med. Poliklinik,, University of Munich, Munich, Germany, 3Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 4Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 5Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, 6Med. Poliklinik, University of Munich, Division of Rheumatology and Clinical Immunology, Munich, Germany, 7University of Munich, Munich, Germany, 8Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 9Dept of Medicine 3, Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, nuclear hormone receptor and systemic sclerosis, T cells

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Pregnane-X-receptor (PXR) belongs to a superfamily of nuclear receptors that function as ligand-activated transcriptional factors. Although endogenous ligands have not yet been identified, PXR is a well-established master regulator of endobiotic metabolism as well as glucose and lipid homeostasis. Herein, we studied the role of PXR in experimental dermal fibrosis.

Methods: Mice were challenged with subcutaneous bleomycin injections and treated with 5-Pregnen-3β-ol-20-one-16α-carbonitrile (PCN) to activate PXR (i.p. once daily, conc. 25 mg/kg). After treatment, murine skin samples were analyzed for skin thickness, hydroxyproline content, α-smooth muscle actin (α-SMA)-positive myofibroblast counts, and phosphorylated smad2/3 (p-smad2/3) levels. Interleukin (IL)-13 was measured by multiplex bead array technology in murine skin. In vitro, murine fibroblasts were treated with PCN prior to stimulation with TGFβ to determine direct effects of PXR on collagen release. To study the release of the Th2 cytokines IL-4 and IL-13 from murine CD4+ T cells, murine T cells were isolated from FVB mice, kept in Th0 and Th2 conditions, and treated with PCN.

Results: We found that PXR activation effectively prevented bleomycin-induced dermal fibrosis as shown by reduced skin thickening (by 85.9 ± 7.5 %; p = 0.002), hydroxyproline content (by 50.5 ± 6.4 %; p = 0.002) and myofibroblast counts (by 77.0 ± 12.0 %; p = 0.005). Apart from preventing fibrosis, PXR stimulation induced regression of established bleomycin-induced dermal fibrosis in a modified treatment model with significant reductions of skin thickening, hydroxyproline content and myofibroblast counts below pre-treatment levels. When elucidating the molecular mechanisms of the anti-fibrotic activity of PXR, we found that PXR activation reduced p-smad2/3 levels by 62.5 ± 9.2 % (p = 0.010) in the skin of bleomycin-challenged mice, suggesting that PXR activity inhibited pro-fibrotic canonical TGF-β signaling. Although PXR was expressed in low levels in dermal fibroblasts, PCN treatment did not change TGF-β-induced collagen release in vitro. This suggested indirect anti-fibrotic effects of PXR on the collagen release from fibroblasts. We therefore examined the effects of PXR stimulation on the release of Th2 cytokines from murine CD4+-positive lymphocytes, which are well-established pro-fibrotic mediators in fibrotic disease. We found that PXR activation reduced the expression of pro-fibrotic TH2 cytokine IL-13 by 60.0 ± 13.1 % (p = 0.010 for 100 µM PCN). Of note, we could confirm these results in vivo since PXR stimulation significantly reduced IL-13 levels by 166 ± 17.3 % (p = 0.001) in the skin from mice challenged with bleomycin.

Conclusion: In summary, we are the first to establish potent anti-fibrotic effects of the nuclear receptor PXR. Pharmacological activation of PXR interferes with IL-13 release from TH2 cells, which leads to inhibition of pro-fibrotic TGF-β signaling and results in decreased fibroblast activation and collagen release. These findings suggest that activation of PXR might be a novel anti-fibrotic approach in particular for early, inflammatory stages of SSc and other fibrotic diseases.


Disclosure:

C. Beyer,
None;

A. Skapenko,
None;

A. Distler,
None;

C. Dees,
None;

H. Reichert,
None;

L. E. Munoz,
None;

J. Leipe,
None;

H. Schulze-Koops,
None;

O. Distler,

Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,

2,

Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,

5,

Actelion, Pfizer and Ergonex,

8;

G. Schett,
None;

J. H. Distler,
None.

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