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.
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
UR - http://www.scopus.com/inward/record.url?scp=0037289786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037289786&partnerID=8YFLogxK
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
SN - 0022-202X
VL - 120
SP - 246
EP - 255
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -