In:
Infection and Immunity, American Society for Microbiology, Vol. 74, No. 10 ( 2006-10), p. 5989-6000
Abstract:
NF-κB is a crucial mediator of macrophage inflammatory responses, but its role in the context of pathogen-induced adaptive immune responses has yet to be elucidated. Here, we demonstrate that classical NF-κB activation delays phagocytosis-induced cell death (PICD) in Raw 264.7 and bone marrow-derived macrophages (BMDMs) upon ingestion of bacteria from the Escherichia coli laboratory strain Top10. By expression of a nondegradable form of IκBα (superrepressor) and pyrrolidine dithiocarbamate treatment, prolonged activation of NF-κB upon bacterial coculture is suppressed, whereas initial induction is only partially inhibited. This activation pattern results in partial inhibition of cellular activation and reduced expression of costimulatory CD86. Notably, suppression of classical NF-κB activation does not influence bacterial uptake rates but is followed by increased production of oxygen radicals and enhanced intracellular killing in Raw macrophages. This is associated with reduced expression of NF-κB-dependent antiapoptotic c-IAP-2 and a loss of the mitochondrial transmembrane potential. Accordingly, NF-κB inhibition in Raw cells and BMDMs causes increased apoptotic rates within 12 h of bacterial ingestion. Interestingly, accelerated eradication of E. coli in NF-κB-inhibited macrophages is associated with reduced antigen-specific T-cell activation in macrophage-lymphocyte cocultures. These data suggest that E. coli inhibits PICD of macrophages via classical, antiapoptotic NF-κB activation and thus facilitates signaling to T cells. Subsequently, a proper adaptive immune response is likely to be generated. Conclusively, therapeutic inhibition of classical NF-κB activation in macrophages may hamper the initiation of adaptive immunity.
Type of Medium:
Online Resource
ISSN:
0019-9567
,
1098-5522
DOI:
10.1128/IAI.00138-06
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2006
detail.hit.zdb_id:
1483247-1
