NF-κB and STAT3 Inhibition as a Therapeutic Strategy in Psoriasis: In Vitro and In Vivo Effects of BTH Rosa M. Andrés, M. Carmen Montesinos, Pedro Navalón,

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NF-κB and STAT3 Inhibition as a Therapeutic Strategy in Psoriasis: In Vitro and In Vivo Effects of BTH Rosa M. Andrés, M. Carmen Montesinos, Pedro Navalón, Miguel Payá, M. Carmen Terencio Journal of Investigative Dermatology Volume 133, Issue 10, Pages 2362-2371 (October 2013) DOI: 10.1038/jid.2013.182 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Inhibitory effect of 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) on NF-κB activation and cytokine release in normal human keratinocytes (NHKs). (a) Chemical structure of BTH. (b) NF-κB electrophoretic mobility shift assay of the nuclear extracts of cultured NHKs. Cells were preincubated with BTH or the reference compound MG-132 (MG) for 30minutes before 1hour of 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation (1μgml−1). One out of five independent experiments is shown. (c) Effect of BTH on tumor necrosis factor α (TNFα) and IL-8 release in NHKs after 7hours of stimulation with TPA (1μgml−1). (d) Effect of BTH on IL-6 and CCL27 release in NHKs after 48hours of stimulation with TNFα (10ngml−1). Dexamethasone (DX, 1μM) was used as reference compound. Values are expressed as mean±SEM (n=6) **P<0.01 versus C. B, nonstimulated cells; c*, 50-fold excess of unlabeled oligonucleotide; C, vehicle-treated stimulated cells. Journal of Investigative Dermatology 2013 133, 2362-2371DOI: (10.1038/jid.2013.182) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 4-Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) impairs keratinocyte proliferation through inhibition of STAT3 phosphorylation. (a) Immunofluorescence staining of total STAT3 (green) in 1-hour IL-6 (50ngml−1)-stimulated normal human keratinocytes (NHKs). Blue color (4′6-diamidino-2-phenylindole) stains cell nuclei. Representative images from three independent experiments. (b) Quantitative analysis of the STAT3 intracellular localization. Results are expressed as % of total fluorescence per cell (n=15) **P<0.01, versus C. (c) Western blotting of phospho-STAT3 in NHKs stimulated with IL-6 (50ngml−1) for 30minutes. One out of three independent experiments is shown. (d) NHK proliferation measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Data are mean absorbance at 490nm±SEM (n=9) *P<0.05, **P<0.01, versus B (vehicle treated). (e) % Toxicity determined as lactate dehydrogenase levels in the supernatants of NHKs cultured for 48hours with BTH. NHKs in vehicle alone (B) or with Triton X-100 (Max) are set as 0% and 100% of cytotoxicity, respectively. Data are mean±SEM (n=9). B, nonstimulated cells; C, vehicle-treated stimulated cells. Bar=50μm. Journal of Investigative Dermatology 2013 133, 2362-2371DOI: (10.1038/jid.2013.182) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Normalization of epidermal hyperplasia and inflammatory cell infiltration after 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) pretreatment in 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation. BTH, dexamethasone (DX), or vehicle (acetone) were topically applied 1hour before TPA administration (2nmol per site) during 3 consecutive days. (a) Macroscopic appearance of the skin at the end of the experiment. (b) Number of infiltrating cells in representative high-power fields (HPFs) and (c) epidermal thickness of hematoxylin and eosin (H&E)–stained tissue sections as mean±SEM (n=6) **P<0.01 versus C. (d) Photomicrographs of H&E staining of skin biopsies. Bar=200μm. (e) Immunofluorescence staining of CD3-positive cells (green, arrows) in skin biopsies. Blue color (4′6-diamidino-2-phenylindole) stains cell nuclei. Bar=50μm. (f) Immunohistochemical detection of cytokeratin 6 (CK6, brown) protein in mouse skin. Bar=50μm. All images are representative from one out of three mice investigated. B, acetone-treated mice; C, acetone and TPA-treated mice. Journal of Investigative Dermatology 2013 133, 2362-2371DOI: (10.1038/jid.2013.182) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Topical treatment with 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) attenuates 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced inflammation and hyperplasia through NF-κB and STAT3 inhibition. BTH, dexamethasone (DX), or vehicle (acetone) were topically applied 1hour before TPA administration (2nmol per site) during 3 consecutive days. (a) Skin edema, assayed as punch biopsy weight. (b) Myeloperoxidase (MPO) activity, (c) leucotriene B4 (LTB4), (d) prostaglandin E2 (PGE2), (e) tumor necrosis factor α (TNFα), (f) CXCL-1, (g) IL-6, and (h) IL-1β levels determined in skin homogenates. Data represent mean±SEM (n=6 animals). *P<0.05, **P<0.01 versus C. (i) NF-κB and STAT3 phosphorylation was assessed by western blotting on protein extracts from skin homogenates. One out of three mice investigated is shown. B, acetone-treated mice; C, acetone and TPA-treated mice. Journal of Investigative Dermatology 2013 133, 2362-2371DOI: (10.1038/jid.2013.182) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 4-Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) ameliorates imiquimod (IMQ)-induced skin inflammation. BTH, dexamethasone (DX) or vehicle (acetone) were topically applied in a delimited area of skin (3cm2) 1hour before IMQ administration. (a) Phenotypical presentation of mouse back skin after 6 days of treatment. (b) Erythema and scaling of the skin was scored daily on a scale from 0 to 4. (c) Hematoxylin and eosin (H&E) staining of skin biopsies. Bar=200μm. (d) BrdU incorporation in keratinocytes was detected by immunohistochemistry. Bar=100μm. (e) Epidermal thickness and (f) number of infiltrating cells in representative high-power fields (HPFs). (g) Myeloperoxidase (MPO) activity and (h) IL-23 levels determined in skin homogenates. (i) NF-κB and STAT3 phosphorylation in skin homogenates. All images are representative from one out of three mice investigated. Data represent mean±SEM (n=6 animals) *P<0.05, **P<0.01 versus C. B, vehicle-treated mice; C, vehicle- and IMQ-treated mice. Journal of Investigative Dermatology 2013 133, 2362-2371DOI: (10.1038/jid.2013.182) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions