Pharmacologic Inhibition of IκB Kinase Activates Immediate Hypersensitivity Reactions in Mice
| Autor: | Dai Miyazaki, Yoshitsugu Inoue, Waka Ishida, Koudai Inata, Atsuki Fukushima, Shin-ichi Sasaki, Takeshi Tominaga, Sachiko Mihara, Keiko Yakura |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.drug_class
cells medicine.medical_treatment Blotting Western Enzyme-Linked Immunosorbent Assay IκB kinase Real-Time Polymerase Chain Reaction environment and public health Pathology and Forensic Medicine Proinflammatory cytokine Mice medicine Animals Secretion Mast Cells skin and connective tissue diseases Protein Kinase Inhibitors Conjunctivitis Allergic B-Lymphocytes Plant Extracts Mast cell activation Chemistry NF-kappa B Degranulation Antigens Plant Receptor antagonist beta-N-Acetylhexosaminidases I-kappa B Kinase Mice Inbred C57BL Hypersensitivity reaction enzymes and coenzymes (carbohydrates) Cytokine Immunology Cancer research Cytokines biological phenomena cell phenomena and immunity Biomarkers |
| Zdroj: | The American Journal of Pathology. 183:96-107 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2013.04.006 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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