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: Dai Miyazaki, Sachiko Mihara, Koudai Inata, Shin-ichi Sasaki, Takeshi Tominaga, Keiko Yakura, Waka Ishida, Atsuki Fukushima, Yoshitsugu Inoue
• Journal: The American journal of pathology (Am J Pathol) Vol. 183 Issue 1 Pg. 96-107 (Jul 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23665348 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Plant
• Biomarkers
• Cytokines
• NF-kappa B
• Plant Extracts
• Protein Kinase Inhibitors
• ragweed pollen
• Chuk protein, mouse
• I-kappa B Kinase
• Ikbkb protein, mouse
• beta-N-Acetylhexosaminidases

Topics

• Animals
• Antigens, Plant (administration & dosage, adverse effects)
• B-Lymphocytes (drug effects, enzymology)
• Biomarkers (metabolism)
• Blotting, Western
• Conjunctivitis, Allergic (enzymology, etiology, immunology)
• Cytokines (metabolism)
• Enzyme-Linked Immunosorbent Assay
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Mast Cells (drug effects, enzymology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Plant Extracts (administration & dosage, adverse effects)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Real-Time Polymerase Chain Reaction
• beta-N-Acetylhexosaminidases (metabolism)