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.

Glycyrrhizin Ameliorates Imiquimod-Induced Psoriasis-like Skin Lesions in BALB/c Mice and Inhibits TNF-a-Induced ICAM-1 Expression via NF-κB/MAPK in HaCaT Cells

“…NF-κB signal modulation is a prominent therapeutic target for inflammatory diseases because aberrantly activated NF-κB signaling contributes to most human skin inflammation disorders [6,18]. TNF-α can activate the NF-κB signaling pathway to induce ICAM-1 expression [17,19].…”

IL-6 as a Druggable Target in Psoriasis: Focus on Pustular Variants

“…Increased activation of STAT3 (pSTAT3) has been detected in lesional skin of psoriatic patients [98]; several cytokines upregulated in psoriasis, including IL-6, IL-20, and IL-22, signal through STAT3 activation [71, 98]. STAT3 phosphorylation influences the expression of genes controlling keratinocyte survival and proliferation through interactions with other transcription factors such as NF-kappaB [96, 99]. STAT3 activation has a key role in the psoriasis-associated IL-23 signaling cascade [71, 97, 99].…”

Isoliquiritigenin prevents the progression of psoriasis-like symptoms by inhibiting NF-κB and proinflammatory cytokines

“…Several components of licorice, such as glycyrrhetinic acid and glycyrrhizin, have been used clinically as an antiallergic and antihepatitis agent in UK and Japan [1]. Although its relatively low contents, ISL, a flavonoids in licorice, has been reported to possess anti-inflammatory, antioxidant, and antitumor properties [9][10][11]36]. Of note, ISL exhibited antitumorigenic activity and estrogen receptor (ER) α-dependent growth promoting effects on breast cancer cells [37].…”