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.