1. ^*Department of Dermatology University of California, San Francisco, San Francisco, California, U.S.A.;
2. ^†Department of Medicine, University of California, San Francisco, U.S.A.;
3. ^‡Department of Medical, University of California, San Francisco, U.S.A.;
4. ^§Department of Dermatology Services, Department of Veteran Affairs Medical Center, San Francisco, California, U.S.A.;
5. ^¶Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina, U.S.A.;
6. ^**Nuclear Receptor Discovery Research, GlaxoSmithKline, Harlow, Essex, U.K.;
7. ^††Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Correspondence: Kenneth R. Feingold, M.D., Metabolism Section (111F), Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121; Email: kfngld@itsa.ucsf.edu

¹Both of these authors contributed equally to this paper.

Received 21 March 2002; Revised 20 September 2002; Accepted 8 October 2002.

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)-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 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 LXR-/- or LXR-/- animals, indicating that LXR is required for this anti-inflammatory effect. 22ROH also caused a partial reduction in ear thickness in LXR-/- 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 pro-inflammatory cytokines interleukin-1 and tumor necrosis factor 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 LXR and LXR. LXR activators could provide a new class of therapeutic agents for the treatment of cutaneous inflammatory disorders.