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

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 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.

Psoriasis: crucial role of LXR-α RNomics

“…[10][11][12] A new dimension was added to understanding the pathognomics of psoriasis by discovering that synthetic LXR-a-specific agonists had the inherent capacity to inhibit cell proliferation in primary epidermal keratinocytes. 13 It is in this context that the results reported here assume importance. Our study unambiguously shows that the LXR-a gene not only regulates the expression of proinflammatory cytokines but also that of VDR, PPAR-g, as well as that of catalase, an antioxidant enzyme responsible for scavenging reactive oxygen species (ROS) within primary epidermal keratinocytes, Figure 3.…”

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

“…We have previously shown that LXR activation inhibits inflammatory responses (5,7,8). In the current work, we show that LXRs are also potent inhibitors of glial cell responses to inflammatory stimuli, including fA␤.…”

“…LXRs are also potent inhibitors of inflammatory responses in macrophages, pointing to an additional function for LXR signaling in immune regulation (5)(6)(7)(8)(9)(10)(11). The function of LXRs in the brain is not well understood.…”

Oxysterol represses high‐affinity IgE receptor‐stimulated mast cell activation in Liver X receptor‐dependent and ‐independent manners

“…Some oxysterols were identified as natural ligands for LXR [4], and have anti-allergic activity; e.g., topical application of LXR-activating oxysterols in mice reduces irritant and allergic cutaneous inflammation [5]. More recently, Heine et al reported that activation of LXRs reduces IgE production from B cells stimulated with anti-CD40 and IL-4 [6].…”