Targeting NF-kappa B with a natural triterpenoid alleviates skin inflammation in a mouse model of psoriasis.
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-kappaB that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3+ lymphocytes show activated NF-kappaB. Since NF-kappaB 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-kappaB targeting would affect the course of the disease in the CD18 hypomorphic (CD18(hypo)) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IkappaB kinase inhibitor acetyl-11-keto-beta-boswellic acid (AKbetaBA), NF-kappaB signaling and the subsequent NF-kappaB-dependent cytokine production as shown by the TNF-alpha 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 AKbetaBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18(hypo) mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-kappaB signaling is pivotal for the pathogenesis in the CD18(hypo) mouse model of psoriasis. Therefore, targeting NF-kappaB might provide an effective strategy for the treatment of psoriasis.
Wang
Honglin
H
Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University Medical School, Shanghai, China.
Syrovets
Tatiana
T
Kess
Daniel
D
Büchele
Berthold
B
Hainzl
Heidi
H
Lunov
Oleg
O
Weiss
Johannes M
JM
Scharffetter-Kochanek
Karin
K
Simmet
Thomas
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D018836:Inflammation Mediators / Q000627:therapeutic use*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D014315:Triterpenes / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D016328:NF-kappa B; D014315:Triterpenes; C094432:acetyl-11-ketoboswellic acid