title: Pharmacologic inhibition of IκB kinase activates immediate hypersensitivity reactions in mice.
abstract: Pharmacologic inhibitors of IκB kinase (IKK), especially IKK-β, 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-β 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-β limits B-cell-mediated mast cell activation and inflammatory cytokine induction in immediate hypersensitivity by counterbalancing the activity of IKK-α.
authors.affiliation: Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Tottori, Japan. dm@grape.med.tottori-u.ac.jp
authors.forename: Dai
authors.initials: D
authors.lastname: Miyazaki
authors.forename: Sachiko
authors.initials: S
authors.lastname: Mihara
authors.forename: Koudai
authors.initials: K
authors.lastname: Inata
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tominaga
authors.forename: Keiko
authors.initials: K
authors.lastname: Yakura
authors.forename: Waka
authors.initials: W
authors.lastname: Ishida
authors.forename: Atsuki
authors.initials: A
authors.lastname: Fukushima
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D000818:Animals; D052179:Antigens, Plant / Q000008:administration & dosage / Q000009:adverse effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D003233:Conjunctivitis, Allergic / Q000201:enzymology* / Q000209:etiology / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D052179:Antigens, Plant; D015415:Biomarkers; D016207:Cytokines; D016328:NF-kappa B; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; C433085:ragweed pollen; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D001619:beta-N-Acetylhexosaminidases