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. 2009 Jul;18(7):643-9.
doi: 10.1111/j.1600-0625.2009.00841.x. Epub 2009 Feb 19.

Activators of PPARs and LXR Decrease the Adverse Effects of Exogenous Glucocorticoids on the Epidermis

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Free PMC article

Activators of PPARs and LXR Decrease the Adverse Effects of Exogenous Glucocorticoids on the Epidermis

Marianne Demerjian et al. Exp Dermatol. .
Free PMC article

Abstract

While glucocorticoids (GC) exert beneficial effects (anti-inflammatory), they also have adverse effects on the epidermis including decreased epidermal differentiation, decreased keratinocyte proliferation, and decreased cutaneous permeability barrier homeostasis. Thus, the purpose of this study was to develop strategies to prevent these GC toxicities using simultaneous topical treatments in clobetasol-treated mice. While a triple-lipid mixture of stratum corneum lipids (ceramide, free fatty acid and cholesterol) was previously shown to reverse the GC-induced abnormality in cutaneous barrier function [J Invest Dermatol, 120 (2003) 456], this lipid mixture did not prevent the GC-induced abnormalities in either keratinocyte proliferation or differentiation. As activators of PPARalpha, beta/delta, gamma and LXR, regulate keratinocyte proliferation and differentiation and improve permeability barrier homeostasis, we next assessed the effects of these activators during concurrent GC treatment. Co-application of either ciglitazone (PPARgamma activator), clofibrate (PPARalpha activator) or 22R (OH) cholesterol (LXR activator) with clobetasol prevented the decrease in involucrin, filaggrin and loricrin expression. By contrast, a PPARbeta/delta activator (GW501516) normalized only the expression of involucrin and filaggrin but not loricrin. Moreover, topical application of PPARalpha, beta/delta or LXR activators partially prevented the decrease in keratinocyte proliferation in GC-treated murine skin, as measured using PCNA, while no effect was seen after co-treatment with PPARgamma activators. Finally, PPARgamma and PPARbeta/delta activators but not PPARalpha and LXR activators improved permeability barrier homeostasis in GC-treated mice. Together, these studies demonstrate that PPAR and LXR activators can prevent several of the adverse effects of topical GC on the epidermis.

Figures

Figure 1
Figure 1. SC triple-lipid mixture does not override the negative effects of GC on keratinocyte differentiation or proliferation
A mixture of physiologic lipids, that includes palmitic acid, cholesterol, and ceramides, applied in a 1 : 1 : 1 mole ratio, did not prevent the GC-induced decrease in expression of the keratinocyte differentiation markers, filaggrin, loricrin and involucrin (A). This lipid mixture also did not prevent the decrease in keratinocyte proliferation observed after GC treatment measured by PCNA staining (B- PCNA cell count: N= 3; PCNA staining: arrows indicate PCNA positive cells).
Figure 2
Figure 2. Improved permeability barrier homeostasis when PPARβ/δ or PPARγ are co-applied with GC
At 3 and 6 hours after barrier disruption permeability barrier recovery was significantly improved when β/δ ligand (GW501516, 4mM) was co-applied with GC (A; N=8). Similar results were obtained at 3, 6 and 24 hours after PPARγ ligand, ciglitazone co-application (B)(N=5).
Figure 3
Figure 3. PPARα and PPARγ activators normalizes differentiation in GC- treated murine skin
As shown in immunohistochemical staining for the keratinocyte differentiation markers, co-application of clofibrate (PPARα ligand)(1mM) with clobetasol normalizes the expression of filaggrin (FIL), involucrin (INV) and loricrin (LOR)(A). Similarly, co-application of ciglitazone (PPARγ activator) (10mM) with clobetasol normalizes these differentiation markers (B). N= 3.
Figure 4
Figure 4. LXR activator normalizes differentiation in GC- treated murine skin
Immunohistochemical staining for the keratinocyte differentiation markers shows that co-application of the LXR activator 22R hydroxycholesterol (10mM) with clobetasol normalizes the expression of filaggrin (FIL), involucrin (INV) and loricrin (LOR). N= 3.
Figure 5
Figure 5. PPARβ/δ activator GW501516 inhibited the decrease in filaggrin and involucrin, but not loricrin expression, on GC- treated murine epidermis
Application of the PPARβ/δ activator GW501516 (4mM) on GC-treated murine epidermis normalized the levels of two keratinocyte differentiation markers, filaggrin (FIL) and involucrin (INV). However, this PPARβ/δ ligand did not prevent the decrease in loricrin (LOR) after GC treatment. N= 3.
Figure 6
Figure 6. PPARα, PPARβ/δ, and LXR activators increase proliferation in GC-treated murine epidermis
Topical application of either PPARα activator (clofibrate, 1mM)(A)(N=3), β/δ ligand (GW501516, 4mM)(B)(N=3) or LXR activator (22R hydroxycholesterol, 10mM)(C, E)(N= 3) increased keratinocyte proliferation in GC-treated murine epidermis, as measured by PCNA. In contrast, no effect on proliferation was seen after ciglitazone (PPARγ ligand) co-treatment (D)(N= 3). All ligands significantly reversed the decrease in the thickness of the epidermal nucleated layers observed after GC treatment (F). The data presented represents the mean of all measured points +/- SEM. (N=31-45).

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