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.
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)-hydroxy-cholesterol (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 approximately 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 nonspecific sterol effect. In addition, 22ROH did not reduce inflammation in LXRbeta-/- or LXRalphabeta-/- animals, indicating that LXRbeta is required for this anti-inflammatory effect. 22ROH also caused a partial reduction in ear thickness in LXRalpha-/- animals, however (approximately 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 (approximately 1.5-fold) in the oxazolone-induced allergic dermatitis model, and 22ROH and GW3965 reduced inflammation by approximately 50% and approximately 30%, respectively. Finally, immunohistochemistry demonstrated an inhibition in the production of the pro-inflammatory cytokines interleukin-1alpha and tumor necrosis factor alpha 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 LXRalpha and LXRbeta. LXR activators could provide a new class of therapeutic agents for the treatment of cutaneous inflammatory disorders.
Fowler
Ashley J
AJ
Department of Dermatology, University of California, San Francisco, USA.
Sheu
Mary Y
MY
Schmuth
Matthias
M
Kao
Jack
J
Fluhr
Joachim W
JW
Rhein
Linda
L
Collins
Jon L
JL
Willson
Timothy M
TM
Mangelsdorf
David J
DJ
Elias
Peter M
PM
Feingold
Kenneth R
KR
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D004268:DNA-Binding Proteins; D017453:Dermatitis, Irritant / Q000276:immunology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006888:Hydroxycholesterols / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010081:Oxazolone / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D007375:Interleukin-1; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; C003585:22-hydroxycholesterol; C007997:25-hydroxycholesterol; D013755:Tetradecanoylphorbol Acetate