title: NF-κB and STAT3 inhibition as a therapeutic strategy in psoriasis: in vitro and in vivo effects of BTH.
abstract: Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) is a simple and interesting synthetic derivative of petrosaspongiolide M, a natural compound isolated from a sea sponge with demonstrated potent anti-inflammatory activity through inhibition of the NF-κB signaling pathway. In the present study, we report the in vitro and in vivo pharmacological effect of BTH on some parameters related to the innate and adaptive response in the pathogenesis of psoriasis. BTH inhibited the release of some of the key psoriatic cytokines such as tumor necrosis factor α, IL-8, IL-6, and CCL27 through the downregulation of NF-κB in normal human keratinocytes. Moreover, it impaired signal transducers and activators of transcription 3 (STAT3) phosphorylation and translocation to the nucleus, which resulted in decreased keratinocyte proliferation. These results were confirmed in vivo in two murine models of psoriasis: the epidermal hyperplasia induced by 12-O-tetradecanoylphorbol-13-acetate and the imiquimod-induced skin inflammation model. In both cases, topical administration of BTH prevented skin infiltration and hyperplasia through suppression of NF-κB and STAT3 phosphorylation. Our results confirm the pivotal role of both transcriptional factors in skin inflammation, as occurs in psoriasis, and highlight the potential of small molecules as therapeutic agents for the treatment of this skin disease, with BTH being a potential candidate for future drug research.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Valencia, Spain; Center of Molecular Recognition and Technological Development, University of Valencia, Valencia, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Andrés
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Valencia, Spain; Center of Molecular Recognition and Technological Development, University of Valencia, Valencia, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Montesinos
authors.affiliation: Department of Urology, General University Hospital of Valencia, Valencia, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Navalón
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Valencia, Spain; Center of Molecular Recognition and Technological Development, University of Valencia, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Payá
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Valencia, Spain; Center of Molecular Recognition and Technological Development, University of Valencia, Valencia, Spain. Electronic address: carmen.terencio@uv.es.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Terencio
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D052816:Foreskin / Q000166:cytology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061251:Primary Cell Culture; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D013830:Thiadiazoles; C099403:S-methyl benzo(1,2,3)thiadiazole-7-carbothioate