The pathogenesis of psoriasis and the mechanism of action of tazarotene.

The 3 major features of psoriasis--abnormal differentiation of keratinocytes, hyperproliferation of keratinocytes, and infiltration of inflammatory components into the skin--can be quantified by measuring levels of certain biochemical markers. Psoriasis is associated with upregulation or downregulation of several of these markers. Tazarotene helps to normalize the levels of the markers, thereby bringing about clinical improvement.

Molecular mechanisms of tazarotene action in psoriasis.

Psoriasis is a chronic immune-mediated disease that is characterized by the hyperproliferation and abnormal differentiation of keratinocytes and by inflammation. The epidermal changes associated with psoriasis may be due to the infiltration of inflammatory T lymphocytes and the release of cytokines in response to antigenic stimulation. Tazarotene is a retinoic acid receptor-specific retinoid with demonstrated efficacy in the topical treatment of psoriasis. Tazarotene down-regulates markers of keratinocyte differentiation, keratinocyte proliferation, and inflammation. The drug also up-regulates three novel genes TIG-1 (tazarotene-induced gene-1), TIG-2, and TIG-3, which may mediate an antiproliferative effect. The effect of tazarotene on these markers is probably a direct effect on gene expression rather than an indirect effect associated with disease improvement.

Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.

Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection. Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor V beta repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific V beta gene, whereas 10 had oligoclonal or polyclonal expansion of several V beta families. All patients with TSST-1+ S aureus had overexpansion of V beta Z in blood and/or skin lesions. These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.

Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis.

Retinoids down-regulate the expression of metalloproteinases, cytokines, and other genes involved in cell proliferation and inflammation. Tazarotene (AGN 190168), a retinoic acid receptor (RAR)-specific retinoid, is effective in the treatment of psoriasis, a hyperproliferative and inflammatory skin disease. Because negative regulation of genes appears to be important in the antiproliferative and antiinflammatory action of retinoids, we studied the down-regulation of genes in skin raft cultures by this antipsoriatic retinoid. By subtraction hybridization, we found that migration inhibitory factor-related protein (MRP-8) and skin-derived anti-leukoproteinase (SKALP) are down-regulated by AGN 190168. MRP-8 and SKALP are overexpressed in psoriatic lesions as compared to the normal epidermis, and they are markers of hyperproliferative keratinocyte differentiation. We also show that MRP-8 expression is retinoid inhibitable in cultured keratinocytes induced to differentiate with 10% serum or IFN-gamma, and that MRP-8 is inhibited by RAR but not by retinoid X receptor-specific retinoids in a dose-dependent manner. Finally, MRP-8, SKALP, and the previously characterized differentiation marker, transglutaminase I, are all down-regulated in vivo in psoriatic lesions after treatment with AGN 190168 in comparison to placebo. Taken together, these data suggest that these markers may be down-regulated by tazarotene in psoriasis through direct action on keratinocyte gene expression rather than by an overall tazarotene effect on lesional therapeutic status.

Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor-responsive gene in skin.

Retinoids exert their effect through ligand-dependent transcription factors, retinoic acid receptors (RARalpha, beta, and gamma) and retinoid X receptor (RXRalpha, beta, and gamma), which belong to the superfamily of steroid/thyroid/vitamin D3, nuclear receptors. Using a subtraction hybridization approach, we have identified a cDNA sequence, Tazarotene Induced Gene 1 (TIG1), which is highly upregulated in skin raft cultures by an RARbeta/gamma -selective retinoid AGN 190168 (tazarotene/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate), which is effective in the treatment of psoriasis. The retinoid-mediated upregulation in the expression of TIG1 was confirmed by Southern and Northern analyses. Upon sequencing, TIG1 was found to be a novel cDNA which encodes a protein of 228 amino acids whose sequence suggests that is a transmembrane protein with a small N-terminal intracellular region, a single membrane-spanning hydrophobic region, and a large C-terminal extracellular region containing a glycosylation signal. We demonstrate that TIG1 is also upregulated by AGN 190168 in skin raft cultures prepared from psoriatic fibroblasts and normal keratinocytes and in primary fibroblast and keratinocyte cultures. We also show that TIG1 is upregulated by retinoic acid receptor but not by retinoid X receptor-specific synthetic retinoids. Finally, we demonstrate that TIG1 is induced by AGN 190168 in psoriatic lesions during the course of clinical treatment of the disease.