Peroxisome Proliferator-Activated Receptor-α Activation Inhibits Langerhans Cell Function

Dubrac, Sandrine; Stoitzner, Patrizia; Pirkebner, Daniela; Elentner, Andreas; Auwerx, Johan; Saeland, Sem; Hengster, Paul; Fritsch, Peter; Romani, Nikolaus; Schmuth, Matthias

doi:10.4049/jimmunol.178.7.4362

Cited by 42 publications

(55 citation statements)

References 57 publications

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“…Furthermore, although both LXRa and LXRb are expressed in cultured human keratinocytes and throughout all layers of the human epidermis (26,34), LXRb is the predominant isoform transcribed in mouse epidermis (35). Finally, all three PPAR isoforms are expressed in human melanocytes in vitro and in epidermal Langerhans cells in vivo (36)(37)(38).…”

Section: Ppar and Lxr Expression In The Skinmentioning

confidence: 99%

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

Schmuth

Jiang

Dubrac

et al. 2008

Journal of Lipid Research

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The epidermis is a very active site of lipid metabolism, and all peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) isoforms are expressed in the epidermis. Activation of PPARa, -b/d, or -g or LXRs stimulates keratinocyte differentiation. Additionally, activation of these receptors also improves permeability barrier homeostasis by a number of mechanisms, including stimulating epidermal lipid synthesis, increasing lamellar body formation and secretion, and increasing the activity of enzymes required for the extracellular processing of lipids in the stratum corneum, leading to the formation of lamellar membranes that mediate permeability barrier function. The stimulation of keratinocyte differentiation and permeability barrier formation also occurs during fetal development, resulting in accelerated epidermal development. PPAR and LXR activation regulates keratinocyte proliferation and apoptosis, and studies have shown that these receptors play a role in cutaneous carcinogenesis. Lastly, PPAR and LXR activation is anti-inflammatory, reducing inflammation in animal models of allergic and irritant contact dermatitis. Because of their broad profile of beneficial effects on skin homeostasis, PPAR and LXR have great potential to serve as drug targets for common skin diseases such as psoriasis, atopic dermatitis, and skin

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Section: Ppar and Lxr Expression In The Skinmentioning

confidence: 99%

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

Schmuth

Jiang

Dubrac

et al. 2008

Journal of Lipid Research

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184

160

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“…Invivo production of cytokines by T lymphocytes was determined as described earlier (21). Alternatively, cells were isolated from spleens by homogenization and stimulated for 48 h. Cells were cultured for 4.5 h with 1 mg/ml Brefeldin A (BD Pharmingen) to prevent cytokine secretion.…”

Section: Cytokine Detectionmentioning

confidence: 99%

“…T lymphocytes were isolated from mouse lymph nodes and spleens as described earlier and further purified by negative selection (21). Purity was 98 6 1% as determined by FACS analysis.…”

Section: Animalsmentioning

confidence: 99%

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Modulation of T Lymphocyte Function by the Pregnane X Receptor

Dubrac

Elentner

Ebner

et al. 2010

The Journal of Immunology

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The pregnane X receptor (PXR) is a ligand-activated transcription factor regulating genes central to drug and hormone metabolism in the liver. Previous reports indicated that PXR is expressed in PBMC, but the role of PXR in immune cells remains unknown. In this paper, we report increased PXR expression in mouse and human T lymphocytes upon immune activation. Furthermore, pharmacologic activation of PXR inhibits T lymphocyte proliferation and anergizes T lymphocytes by decreasing the expression of CD25 and IFN-γ and decreasing phosphorylated NF-κB and MEK1/2. Although these effects are preceded by an increase of suppressor of cytokine signaling 1, a master switch for IFN-γ expression, in a PXR-dependent manner, T-bet expression remains unchanged. Conversely, PXR-deficient mice exhibit an exaggerated T lymphocyte proliferation and increased CD25 expression. Furthermore, PXR-deficient lymphocytes produce more IFN-γ and less of the anti-inflammatory cytokine IL-10. In summary, these results reveal a novel immune-regulatory role of PXR in T lymphocytes and identify suppressor of cytokine signaling 1 as an early signal in PXR-mediated T lymphocyte suppression.

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Lack of IL‐2 in PPAR‐α‐deficient mice triggers allergic contact dermatitis by affecting regulatory T cells

et al. 2011

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The aim of the present work was to decipher the cellular basis of the immunoregulatory role of peroxisome proliferator-activated receptor (PPAR)-a in cutaneous hypersensitivity reactions. After challenge with a contact allergen, we observed augmented hypersensitivity reactions with increased numbers of activated T lymphocytes in the skin of PPAR-a À/À mice.Furthermore, following antigen challenge, the percentages of Tregs in the blood, draining lymph nodes and skin were decreased in these mice. PPAR-a deficiency impaired the production of IL-2 in lymph nodes, whereas TGF-b levels remained unchanged. Injection of IL-2 into PPAR-a À/À mice restored the Treg population in the skin-draining lymph nodes of allergen-challenged mice. In vivo induction of Tregs from WT CD4 1 CD25 À T cells was impaired when adoptively transferred into PPAR-a À/À mice as compared with transfer into WT mice, and reversed by injection of IL-2 into PPAR-a À/À mice. Furthermore, the suppressive capacity of PPAR-a À/À Tregs was impaired when compared to WT Tregs in vitro and in co-adoptive transfer experiments. Finally, injection of IL-2 to PPAR-a À/À mice decreased skin inflammation to a level similar to WT mice. In conclusion, the pro-inflammatory skin phenotype of PPAR-a À/À mice is due to lack of IL-2-mediated Treg induction in these mice.Key words: Inflammation . Nuclear hormone receptors . Skin Supporting Information available online IntroductionPeroxisome proliferator-activated receptor (PPAR)-a is a nuclear hormone receptor that, upon heterodimerization with the retinoid X receptor (RXR), functions as a transcriptional regulator of glucose and lipid metabolism [1]. Fatty acid, fibrates and eicosanoids are ligands of . PPAR-a is highly expressed in the liver, heart, muscle, kidney and arterial blood vessels. Furthermore, it has been shown that PPAR-a is expressed in cells of the immune system, including B and T lymphocytes, monocytes/macrophages, DCs and epidermal Langerhans cells [5][6][7]. Since PPAR-a is expressed in all key cells of the adaptive immune system and since specific PPAR-a ligands have been identified, the immune-regulatory role of PPAR-a can now be explored in depth. Previous work has shown that PPAR-a is strongly linked to inflammatory reactions. For example, inflammatory stimuli such as lipopolysaccharide and TNF-a activate NF-kB, a major transcription factor mediating inflammation by promoting the secretion of inflammatory cytokines. PPAR-a ligands can block the NF-kB pathway, and thereby modulate the immune response [7,8].Since PPAR-a activation exerts anti-inflammatory effects [8][9][10], it can be hypothesized that PPAR-a deficiency leads to a 10.1002/eji.201041357 Eur. J. Immunol. 2011. 41: 1980-1991 Sandrine Dubrac et al. 1980 pro-inflammatory phenotype. Indeed, after induction of experimental autoimmune encephalomyelitis, PPAR-a-deficient mice develop more severe clinical symptoms than control mice in a gender-dependent manner [11]. In these experiments, the authors also found a higher capacity of PPAR-...

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Peroxisome Proliferator-Activated Receptor-α Activation Inhibits Langerhans Cell Function

Cited by 42 publications

References 57 publications

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

Modulation of T Lymphocyte Function by the Pregnane X Receptor

Lack of IL‐2 in PPAR‐α‐deficient mice triggers allergic contact dermatitis by affecting regulatory T cells

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