| First Author | Miyazaki D | Year | 2013 |
| Journal | Am J Pathol | Volume | 183 |
| Issue | 1 | Pages | 96-107 |
| PubMed ID | 23665348 | Mgi Jnum | J:197438 |
| Mgi Id | MGI:5492307 | Doi | 10.1016/j.ajpath.2013.04.006 |
| Citation | Miyazaki D, et al. (2013) Pharmacologic Inhibition of IkappaB Kinase Activates Immediate Hypersensitivity Reactions in Mice. Am J Pathol 183(1):96-107 |
| abstractText | Pharmacologic inhibitors of IkappaB kinase (IKK), especially IKK-beta, have been developed to treat inflammatory diseases. However, their interactions with components of the NF-kappaB 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-kappaB 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-kappaB promoter in isolated B cells was induced exclusively by IKK-beta inhibition and was negated by ablating IKK-alpha. Aggravated mast cell degranulation by pharmacologic IKK inhibition in the murine immediate hypersensitivity reaction was corrected by B-cell-targeted inhibition of IKK-alpha. Thus, IKK-beta limits B-cell-mediated mast cell activation and inflammatory cytokine induction in immediate hypersensitivity by counterbalancing the activity of IKK-alpha. |
