TY - JOUR
T1 - Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models
T2 - Liver-X-receptor-specific inhibition of inflammation and primary cytokine production
AU - Fowler, Ashley J.
AU - Sheu, Mary Y.
AU - Schmuth, Matthias
AU - Kao, Jack
AU - Fluhr, Joachim W.
AU - Rhein, Linda
AU - Collins, Jon L.
AU - Willson, Timothy M.
AU - Mangelsdorf, David J.
AU - Elias, Peter M.
AU - Feingold, Kenneth R.
N1 - Funding Information:
David J. Mangelsdorf, M.D., is funded by the Howard Hughes Medical Institute and the Robert A. Welch Foundation. This work was supported by NIH grants HD 29706, AR 29706, and PO 039448, and by the Veterans Affairs Research Funding.
PY - 2003/2/1
Y1 - 2003/2/1
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.
AB - 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.
KW - Inflammation
KW - Keratinocyte
KW - Nuclear hormone receptors
KW - Oxysterols
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U2 - 10.1046/j.1523-1747.2003.12033.x
DO - 10.1046/j.1523-1747.2003.12033.x
M3 - Article
C2 - 12542530
AN - SCOPUS:0037289786
VL - 120
SP - 246
EP - 255
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 2
ER -