Inhibition of tumour necrosis factor-α secretion from EpiDermTM tissues by a novel small molecule, UTL-5d.

Background  UTL-5d [ N-(4-chlorophenyl)-3-carboxyamidyl-5-methylisoxazole] is a small-molecule tumour necrosis factor (TNF)-α modulator being investigated for its potential in several immune-mediated diseases, including psoriasis. Objectives  We aimed to determine whether UTL-5d represents a potential antipsoriasis agent. Methods  Firstly, a keratinocyte cell-based study was used to study the inhibition of TNF-α and gene suppression by UTL-5d in vitro. Secondly, a multilayered human epidermis tissue model, consisting of normal human-derived epidermal keratinocytes, was used to study the dose-dependent reduction of TNF-α by UTL-5d as well as the feasibility of using UTL-5d in a lotion formulation. Results  The cell-based study showed that UTL-5d significantly reduced TNF-α secretion from keratinocytes (68% reduction at 17 μg mL−1) and suppressed JAK3 and MAP3K2 genes by 70% and 40%, respectively. In the human epidermis tissue model, reduction of TNF-α by UTL-5d appeared to be dose dependent (8·35–33·4 μg mL−1); UTL-5d also reduced cell death induced by ultraviolet (UV) B. Tissues treated by UTL-5d in a preliminary lotion formulation showed significant reduction of TNF-α induced by UVB. Conclusions  Our results indicate that UTL-5d may be worthy of further investigation for its potential as a topical agent for psoriasis. [ABSTRACT FROM AUTHOR]