title: Interleukin-1 alpha blockade prevents hyperkeratosis in an in vitro model of lamellar ichthyosis.
abstract: The autosomal recessive congenital ichthyoses are a family of related diseases, causing a severe defect in the barrier function of the epidermis. Neonates are usually born as collodion babies, but later form scales characteristic of the disease, due to a combination of thickening of the cornified layer and an increase in the production of non-polar lipids. Current treatments of choice are exfoliative creams and moisturizing agents and the use of oral retinoids. The skin condition and treatment impact significantly on quality of life and, with oral retinoids, there are potential complications associated with long-term use. A greater understanding of the mechanisms that result in scaling should lead to better directed therapies, not only for the inherited ichthyoses, but also other hyperkeratotic disorders. Using siRNA knockdown of the principle gene mutated in lamellar ichthyosis (LI), transglutaminase-1, in rat keratinocytes, we created an in vitro organotypic culture model that closely mimics the disease. Interleukin-1 alpha (IL1A) expression was increased and there was a lack of loricrin cross-linking. All LI patients tested had an increased IL1A and treatment of wild-type organotypic cultures with IL1A was sufficient to induce hyperkeratosis. Treatment of disease mimic organotypic cultures with IL-1 receptor antagonist led to a dose-dependent decrease in hyperkeratosis without a reduction in non-polar lipids in the cornified layer, which has the potential to reduce scaling without the requirement to constantly apply emollients.
authors.affiliation: Department of Immunobiology and Dermatology, UCL Institute of Child Health, and Department of Paediatric Dermatology, Great Ormond Street Hospital for Sick Children, London, UK. r.oshaughnessy@ich.ucl.ac.uk
authors.forename: Ryan F L
authors.initials: RF
authors.lastname: O'Shaughnessy
authors.forename: Ishaan
authors.initials: I
authors.lastname: Choudhary
authors.forename: John I
authors.initials: JI
authors.lastname: Harper
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000378:metabolism / Q000628:therapy*; D007231:Infant, Newborn; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D009924:Organ Culture Techniques; D051381:Rats; D012867:Skin / Q000473:pathology; D011503:Transglutaminases / Q000172:deficiency
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D008565:Membrane Proteins; C064554:loricrin; D011503:Transglutaminases; C105804:transglutaminase 1