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Pharmacologic inhibition of IκB kinase activates immediate hypersensitivity reactions in mice.
Miyazaki, Dai; Mihara, Sachiko; Inata, Koudai; Sasaki, Shin-ichi; Tominaga, Takeshi; Yakura, Keiko; Ishida, Waka; Fukushima, Atsuki; Inoue, Yoshitsugu.
Afiliação
  • Miyazaki D; Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Tottori, Japan. dm@grape.med.tottori-u.ac.jp
Am J Pathol ; 183(1): 96-107, 2013 Jul.
Article em En | MEDLINE | ID: mdl-23665348
Pharmacologic inhibitors of IκB kinase (IKK), especially IKK-ß, have been developed to treat inflammatory diseases. However, their interactions with components of the NF-κB pathways are not fully known in allergic diseases. To examine whether IKK is involved in immediate hypersensitivity reactions and to determine whether counterregulatory mechanisms in the NF-κB activation system were active, we examined the role played by IKK components on mast cell degranulation using a murine ocular immediate hypersensitivity reaction model. Pharmacologic inhibition of IKK in mice caused paradoxical aggravation of the mast cell-mediated immediate hypersensitivity reaction and up-regulation in the expression of inflammatory cytokines. Downstream analyses showed that B-cell deficiency or treatment by IL-1 receptor antagonist corrected the aberrant activation of tissue-resident mast cells, which would indicate contribution by activated B cells. Analyses of co-cultures of tissue-resident mast cells showed the contribution of activated B cells to activation of mast cells and secretion of inflammatory cytokines. Aberrant activation of the NF-κB promoter in isolated B cells was induced exclusively by IKK-ß inhibition and was negated by ablating IKK-α. Aggravated mast cell degranulation by pharmacologic IKK inhibition in the murine immediate hypersensitivity reaction was corrected by B-cell-targeted inhibition of IKK-α. Thus, IKK-ß limits B-cell-mediated mast cell activation and inflammatory cytokine induction in immediate hypersensitivity by counterbalancing the activity of IKK-α.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Conjuntivite Alérgica / Linfócitos B / Quinase I-kappa B / Mastócitos Tipo de estudo: Etiology_studies / Evaluation_studies / Prognostic_studies Limite: Animals Idioma: En Revista: Am J Pathol Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Conjuntivite Alérgica / Linfócitos B / Quinase I-kappa B / Mastócitos Tipo de estudo: Etiology_studies / Evaluation_studies / Prognostic_studies Limite: Animals Idioma: En Revista: Am J Pathol Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Japão