Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

Abstract

Psoriasis vulgaris is a common chronic inflammatory skin disease involving cytokines and an activated cellular immune system. At variance to skin from patients with atopic dermatitis or from healthy subjects, human psoriatic skin lesions exhibit strong activation of transcription factor NF-κB that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3+ lymphocytes show activated NF-κB. Since NF-κB signaling is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis, we investigated whether NF-κB targeting would affect the course of the disease in the CD18 hypomorphic (CD18hypo) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IκB kinase inhibitor acetyl-11-keto-β-boswellic acid (AKβBA), NF-κB signaling and the subsequent NF-κB-dependent cytokine production as shown by the TNF-α production of macrophages were profoundly suppressed. Additionally, application of the compound counteracted the intradermal MCP-1, IL-12, and IL-23 expression in previously lesional skin areas, led to resolution of the abundant immune cell infiltrates, and significantly reduced the increased proliferation of the keratinocytes. Overall, the AKβBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18hypo mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-κB signaling is pivotal for the pathogenesis in the CD18hypo mouse model of psoriasis. Therefore, targeting NF-κB might provide an effective strategy for the treatment of psoriasis.

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

“…50053-M08H), 15 ng/ml, was injected intracutaneously every other day during IMQ treatment (injection volume 75 ml) (27,28). Control mice were injected with 75 ml PBS, the solvent of recombinant protein.…”

Drug Repurposing by Simulating Flow Through Protein–Protein Interaction Networks

“…This cytokine and activated signaling pathway plays an essential role in the pathogenesis of psoriasis. Additionally, most drugs indicated for the treatment of psoriasis alter NFκB activity and the examination of this pathway is the focus of drug discovery for the disease 18, 19, 20, 21. Thus, the effect of different drug concentrations on TNF‐induced NFκB activity was measured in our experiments using a dual‐luciferase reporter assay.…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…In addition, AKBA can enhance the apoptosis induced by TNF-a and some chemotherapeutic agents, as well as inhibit invasion through inhibition of NF-jB activity, and subsequent downregulation of Bcl-2 and Bcl-xL in prostate cancer cell line PC-3 [71,79]. Topical application of BA exhibited significant anti-inflammatory and pro-apoptotic activity in animal models of inflammation and is currently being tested in clinical trials [80][81][82]. These observations support the use of BA and AKBA for both prevention and treatment of inflammation driven cancers.…”