Inhibition of tumour necrosis factor-alpha 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)-alpha modulator being investigated for its potential in several immune-mediated diseases, including psoriasis.


OBJECTIVE
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-alpha 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-alpha 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-alpha secretion from keratinocytes (68% reduction at 17 mug mL(-1)) and suppressed JAK3 and MAP3K2 genes by 70% and 40%, respectively. In the human epidermis tissue model, reduction of TNF-alpha by UTL-5d appeared to be dose dependent (8.35-33.4 microg 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-alpha 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.
Shaw
J
J
Unitech Pharmaceuticals, Inc., 4370 Varsity Drive, Ann Arbor, MI 48108, USA. shaw@unitechpharma.com
Liu
C
C
Martin
R
R
Chen
B
B
Holtz
R
R
Huang
W-H
WH
Lee
A-R
AR
D001692:Biological Transport; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007166:Immunosuppressive Agents; D007555:Isoxazoles; C526239:N-(4-chlorophenyl)-3-carboxyamidyl-5-methylisoxazole; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D053616:Janus Kinase 3