Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: Liver-X-receptor-specific inhibition of inflammation and primary cytokine production

Ashley J. Fowler, Mary Sheu, Matthias Schmuth, Jack Kao, Joachim W. Fluhr, Linda Rhein, Jon L. Collins, Timothy M. Willson, David J. Mangelsdorf, Peter M. Elias, Kenneth R. Feingold

Research output: Contribution to journalArticle

Abstract

Activators of liver X receptors (LXR) stimulate epidermal differentiation and development, but inhibit keratinocyte proliferation. In this study, the anti-inflammatory effects of two oxysterols, 22(R)-hydroxycholesterol (22ROH) and 25-hydroxycholesterol (25OH), and a nonsterol activator of LXR, GW3965, were examined utilizing models of irritant and allergic contact dermatitis. Irritant dermatitis was induced by applying phorbol 12-myristate-13-acetate(TPA) to the surface of the ears of CD1 mice, followed by treatment with 22ROH, 25OH, GW3965, or vehicle alone. Whereas TPA treatment alone induced an ≈2-fold increase in ear weight and thickness, 22ROH, 25OH, or GW3965 markedly suppressed the increase (greater than 50% decrease), and to an extent comparable to that observed with 0.05% clobetasol treatment. Histology also revealed a marked decrease in TPA-induced cutaneous inflammation in oxysterol-treated animals. As topical treatment with cholesterol did not reduce the TPA-induced inflammation, and the nonsterol LXR activator (GW3965) inhibited inflammation, the anti-inflammatory effects of oxysterols cannot be ascribed to a non-specific sterol effect. In addition, 22ROH did not reduce inflammation in LXRβ -/- or LXRαβ -/- animals, indicating that LXRβ is required for this anti-inflammatory effect. 22ROH also caused a partial reduction in ear thickness in LXRα -/- animals, however (≈50% of that observed in wild-type mice), suggesting that this receptor also mediates the anti-inflammatory effects of oxysterols. Both ear thickness and weight increased (≈1.5-fold) in the oxazolone-induced allergic dermatitis model, and 22ROH and GW3965 reduced inflammation by ≈50% and ≈30%, respectively. Finally, immunohistochemistry demonstrated an inhibition in the production of the proinflammatory cytokines interleukin-1α and tumor necrosis factor α in the oxysterol-treated sites from both TPA- and oxazolone-treated animals. These studies demonstrate that activators of LXR display potent anti-inflammatory activity in both irritant and allergic contact models of dermatitis, requiring the participation of both LXRα and LXRβ. LXR activators could provide a new class of therapeutic agents for the treatment of cutaneous inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)246-255
Number of pages10
JournalJournal of Investigative Dermatology
Volume120
Issue number2
DOIs
StatePublished - Feb 1 2003
Externally publishedYes

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Dermatitis
Allergic Contact Dermatitis
Irritants
Liver
Anti-Inflammatory Agents
Cytokines
Inflammation
Ear
Animals
Oxazolone
Liver X Receptors
Therapeutics
Clobetasol
Irritant Dermatitis
Weights and Measures
Skin
Histology
Sterols
Interleukin-1
Keratinocytes

Keywords

  • Inflammation
  • Keratinocyte
  • Nuclear hormone receptors
  • Oxysterols

ASJC Scopus subject areas

  • Dermatology

Cite this

Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models : Liver-X-receptor-specific inhibition of inflammation and primary cytokine production. / Fowler, Ashley J.; Sheu, Mary; Schmuth, Matthias; Kao, Jack; Fluhr, Joachim W.; Rhein, Linda; Collins, Jon L.; Willson, Timothy M.; Mangelsdorf, David J.; Elias, Peter M.; Feingold, Kenneth R.

In: Journal of Investigative Dermatology, Vol. 120, No. 2, 01.02.2003, p. 246-255.

Research output: Contribution to journalArticle

Fowler, Ashley J. ; Sheu, Mary ; Schmuth, Matthias ; Kao, Jack ; Fluhr, Joachim W. ; Rhein, Linda ; Collins, Jon L. ; Willson, Timothy M. ; Mangelsdorf, David J. ; Elias, Peter M. ; Feingold, Kenneth R. / Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models : Liver-X-receptor-specific inhibition of inflammation and primary cytokine production. In: Journal of Investigative Dermatology. 2003 ; Vol. 120, No. 2. pp. 246-255.
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abstract = "Activators of liver X receptors (LXR) stimulate epidermal differentiation and development, but inhibit keratinocyte proliferation. In this study, the anti-inflammatory effects of two oxysterols, 22(R)-hydroxycholesterol (22ROH) and 25-hydroxycholesterol (25OH), and a nonsterol activator of LXR, GW3965, were examined utilizing models of irritant and allergic contact dermatitis. Irritant dermatitis was induced by applying phorbol 12-myristate-13-acetate(TPA) to the surface of the ears of CD1 mice, followed by treatment with 22ROH, 25OH, GW3965, or vehicle alone. Whereas TPA treatment alone induced an ≈2-fold increase in ear weight and thickness, 22ROH, 25OH, or GW3965 markedly suppressed the increase (greater than 50{\%} decrease), and to an extent comparable to that observed with 0.05{\%} clobetasol treatment. Histology also revealed a marked decrease in TPA-induced cutaneous inflammation in oxysterol-treated animals. As topical treatment with cholesterol did not reduce the TPA-induced inflammation, and the nonsterol LXR activator (GW3965) inhibited inflammation, the anti-inflammatory effects of oxysterols cannot be ascribed to a non-specific sterol effect. In addition, 22ROH did not reduce inflammation in LXRβ -/- or LXRαβ -/- animals, indicating that LXRβ is required for this anti-inflammatory effect. 22ROH also caused a partial reduction in ear thickness in LXRα -/- animals, however (≈50{\%} of that observed in wild-type mice), suggesting that this receptor also mediates the anti-inflammatory effects of oxysterols. Both ear thickness and weight increased (≈1.5-fold) in the oxazolone-induced allergic dermatitis model, and 22ROH and GW3965 reduced inflammation by ≈50{\%} and ≈30{\%}, respectively. Finally, immunohistochemistry demonstrated an inhibition in the production of the proinflammatory cytokines interleukin-1α and tumor necrosis factor α in the oxysterol-treated sites from both TPA- and oxazolone-treated animals. These studies demonstrate that activators of LXR display potent anti-inflammatory activity in both irritant and allergic contact models of dermatitis, requiring the participation of both LXRα and LXRβ. LXR activators could provide a new class of therapeutic agents for the treatment of cutaneous inflammatory disorders.",
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T2 - Liver-X-receptor-specific inhibition of inflammation and primary cytokine production

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AU - Schmuth, Matthias

AU - Kao, Jack

AU - Fluhr, Joachim W.

AU - Rhein, Linda

AU - Collins, Jon L.

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AU - Mangelsdorf, David J.

AU - Elias, Peter M.

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N2 - Activators of liver X receptors (LXR) stimulate epidermal differentiation and development, but inhibit keratinocyte proliferation. In this study, the anti-inflammatory effects of two oxysterols, 22(R)-hydroxycholesterol (22ROH) and 25-hydroxycholesterol (25OH), and a nonsterol activator of LXR, GW3965, were examined utilizing models of irritant and allergic contact dermatitis. Irritant dermatitis was induced by applying phorbol 12-myristate-13-acetate(TPA) to the surface of the ears of CD1 mice, followed by treatment with 22ROH, 25OH, GW3965, or vehicle alone. Whereas TPA treatment alone induced an ≈2-fold increase in ear weight and thickness, 22ROH, 25OH, or GW3965 markedly suppressed the increase (greater than 50% decrease), and to an extent comparable to that observed with 0.05% clobetasol treatment. Histology also revealed a marked decrease in TPA-induced cutaneous inflammation in oxysterol-treated animals. As topical treatment with cholesterol did not reduce the TPA-induced inflammation, and the nonsterol LXR activator (GW3965) inhibited inflammation, the anti-inflammatory effects of oxysterols cannot be ascribed to a non-specific sterol effect. In addition, 22ROH did not reduce inflammation in LXRβ -/- or LXRαβ -/- animals, indicating that LXRβ is required for this anti-inflammatory effect. 22ROH also caused a partial reduction in ear thickness in LXRα -/- animals, however (≈50% of that observed in wild-type mice), suggesting that this receptor also mediates the anti-inflammatory effects of oxysterols. Both ear thickness and weight increased (≈1.5-fold) in the oxazolone-induced allergic dermatitis model, and 22ROH and GW3965 reduced inflammation by ≈50% and ≈30%, respectively. Finally, immunohistochemistry demonstrated an inhibition in the production of the proinflammatory cytokines interleukin-1α and tumor necrosis factor α in the oxysterol-treated sites from both TPA- and oxazolone-treated animals. These studies demonstrate that activators of LXR display potent anti-inflammatory activity in both irritant and allergic contact models of dermatitis, requiring the participation of both LXRα and LXRβ. LXR activators could provide a new class of therapeutic agents for the treatment of cutaneous inflammatory disorders.

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