RESUMO
BACKGROUND: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems. OBJECTIVE: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD). METHODS: A total of 104 ambulatory patients with mild to moderate AD were enrolled in this randomized, double-blind, vehicle-controlled trial between December 2015 and September 2016. VTP-38543 cream in 3 concentrations (0.05%, 0.15%, and 1.0%) or placebo was applied twice daily for 28 days. Pretreatment and posttreatment skin biopsy specimens were obtained from a subset of 33 patients. Changes in SCORing of Atopic Dermatitis, Eczema Area and Severity Index, Investigator's Global Assessment, and tissue biomarkers (by real-time polymerase chain reaction and immunostaining) were evaluated. RESULTS: Topical VTP-38543 was safe and well tolerated. VTP-38543 significantly increased messenger RNA (mRNA) expression of epidermal barrier differentiation (loricrin and filaggrin, P = .02) and lipid (adenosine triphosphate-binding cassette subfamily G member 1 and sterol regulatory element binding protein 1c, P < .01) measures and reduced epidermal hyperplasia markers (thickness, keratin 16 mRNA). VTP-38543 nonsignificantly suppressed cellular infiltrates and down-regulated mRNA expression of several TH17/TH22-related (phosphatidylinositol 3, S100 calcium-binding protein A12) and innate immunity (interleukin 6) markers. CONCLUSION: Topical VTP-38543 is safe and well tolerated. Its application led to improvement in barrier differentiation and lipids. Longer-term studies are needed to clarify whether a barrier-based approach can induce meaningful suppression of immune abnormalities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02655679.
Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Epiderme/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Receptores X do Fígado/agonistas , RNA Mensageiro/agonistas , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/imunologia , Administração Cutânea , Adulto , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/imunologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Método Duplo-Cego , Epiderme/imunologia , Epiderme/patologia , Feminino , Proteínas Filagrinas , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , Queratina-16/genética , Queratina-16/imunologia , Receptores X do Fígado/genética , Receptores X do Fígado/imunologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Proteína S100A12/genética , Proteína S100A12/imunologia , Índice de Gravidade de Doença , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Chronic inflammation of psoriatic lesions may be due to an exaggerated innate immune response. Toll-like receptors (TLRs) are expressed by keratinocytes in psoriasis. Antikeratin 16 autoantibodies (AK16 autoAbs) are increased in serum from patients with psoriasis. Whether the elevated AK16 autoAbs play a role in psoriasis by exaggerating innate immune response is still unknown. OBJECTIVE: To prove that AK16 autoAbs are involved in psoriasis, by exaggerating the innate immune response of keratinocytes. METHODS: Keratinocytes were incubated with mouse antikeratin 16 monoclonal antibodies (AK16 mAbs) for a given length of time. Levels of TLR2, TLR4, involucrin and nascent polypeptide-associated complex (NACA) mRNA were measured by quantitative RT-PCR. Levels of TLR2, TLR4, involucrin, NF-kappaB and actin-related protein 2 (ARP2) protein were measured by flow cytometry or Western blot. Effects of the mAbs on keratinocytes were studied using DNA synthesis and cell cycle analysis. RESULTS: TLR2 mRNA increased 1.73-, 1.60- and 2.52-fold at 6, 24 and 36 h after incubation, respectively. TLR4 mRNA increased 3.62- and 2.21-fold after 12 and 36 h. Involucrin mRNA increased 2.33- and 2.0-fold after 12 and 36 h. NACA mRNA increased 5.93-, 3.35- and 3.54-fold after 12, 24 and 36 h. TLR2 protein increased 1.73-fold on the cell membrane and 2.22-fold on membrane plus intracytoplasm. NF-kappaB increased 2.64-fold after 6 h. Involucrin protein increased 4.5-fold, whereas Arp2 protein decreased 1.82-fold, after 36 h. The mAbs had an inhibitory effect on cultured keratinocytes. CONCLUSION: AK16 autoAbs may be involved in the chronic inflammation of psoriasis lesions by promoting TLR expression.