GS143, an IkappaB ubiquitination inhibitor, inhibits allergic airway inflammation in mice.
Asthma is characterized by airway inflammation with intense eosinophil infiltration and mucus hyper-production, in which antigen-specific Th2 cells play critical roles. Nuclear factor-kappaB (NF-kappaB) pathway has been demonstrated to be essential for the production of Th2 cytokines and chemokines in the airways in murine asthma models. In the present study, we examined the effect of GS143, a novel small-molecule inhibitor of IkappaB ubiquitination, on antigen-induced airway inflammation and Th2 cytokine production in mice. Intranasal administration of GS143 prior to antigen challenge suppressed antigen-induced NF-kappaB activation in the lung of sensitized mice. Intranasal administration of GS143 also inhibited antigen-induced eosinophil and lymphocyte recruitment into the airways as well as the expression of Th2 cytokines and eotaxin in the airways. Moreover, GS143 inhibited antigen-induced differentiation of Th2 cells but not of Th1 cells in vitro. Taken together, these results suggest that IkappaB ubiquitination inhibitor may have therapeutic potential against asthma.
Hirose
Koichi
K
Department of Allergy and Clinical Immunology, Chiba University Hospital, Japan.
Wakashin
Hidefumi
H
Oki
Mie
M
Kagami
Shin-ichiro
S
Suto
Akira
A
Ikeda
Kei
K
Watanabe
Norihiko
N
Iwamoto
Itsuo
I
Furuichi
Yasuhiro
Y
Nakajima
Hiroshi
H
D000281:Administration, Intranasal; D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D001249:Asthma / Q000276:immunology / Q000517:prevention & control*; D001565:Benzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D054875:Ubiquitination / Q000187:drug effects*
C527646:4-(3-benzyl-4-(5-(2-fluorophenyl)-ruan-2-ylmethylene)-5-oxo-4,5-dihydropyrazol-1-yl)benzoic acid; D000941:Antigens; D001565:Benzoates; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011720:Pyrazoles