Topical application with a new NF-kappaB inhibitor improves atopic dermatitis in NC/NgaTnd mice.
Growing evidence has demonstrated the crucial role of NF-kappaB activation on disease severity in allergic disorders. In this study, we examined the clinical relevance of a novel NF-kappaB inhibitor, IMD-0354, for atopic dermatitis (AD) by its topical application. To investigate the in vivo efficacy, 1% IMD-0354 ointment was applied daily to NC/NgaTnd mice with severe dermatitis, which served as a model for human AD. During 2 weeks of treatment, scratching behavior decreased and severity of dermatitis reduced in mice treated with IMD-0354 as well as FK506 without diverse effects. Based on histological examinations, the hyperplasia of keratinocytes and infiltration of inflammatory cells were significantly reduced in the skin of IMD-0354-treated mice. The expressions of T-helper 2 cytokines and tumor necrosis factor-alpha at the affected skin sites were downregulated in IMD-0354-treated mice. Furthermore, IMD-0354 suppressed the proliferation of various immunocompetent cells, neurite outgrowth of nerve growth factor-stimulated pheochromocytoma cells, IgE production from splenic B cells, and IgE-mediated activation of mast cells in vitro. IMD-0354 effectively reduced the allergic inflammation in NC/NgaTnd mice in vivo. Thus, a drug that interferes with NF-kappaB activity may provide an alternative therapeutic strategy for the treatment of AD.
Tanaka
Akane
A
Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Graduate School, Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
Muto
Susumu
S
Jung
Kyungsook
K
Itai
Akiko
A
Matsuda
Hiroshi
H
D000287:Administration, Topical; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000473:pathology* / Q000503:physiopathology*; D015536:Down-Regulation; D007121:Immunocompetence; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D016501:Neurites / Q000187:drug effects; D009824:Ointments; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013154:Spleen; D016559:Tacrolimus / Q000494:pharmacology; D018418:Th2 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001549:Benzamides; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D009824:Ointments; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D016559:Tacrolimus