Prolonged classical NF-kappaB activation prevents autophagy upon E. coli stimulation in vitro: a potential resolving mechanism of inflammation.
Activation of NF-kappaB is known to prevent apoptosis but may also act as proapoptotic factor in order to eliminate inflammatory cells. Here, we show that classical NF-kappaB activation in RAW 264.7 and bone marrow-derived macrophages upon short E. coli coculture is necessary to promote cell death at late time points. At 48 hours subsequent to short-term, E. coli challenge increased survival of NF-kappaB-suppressed macrophages was associated with pattern of autophagy whereas macrophages with normal NF-kappaB signalling die. Cell death of normal macrophages was indicated by preceding downregulation of autophagy associated genes atg5 and beclin1. Restimulation of macrophages with LPS at 48 hours after E. coli treatment results in augmented proinflammatory cytokine production in NF-kappaB-suppressed macrophages compared to control cells. We thus demonstrate that classical NF-kappaB activation inhibits autophagy and promotes delayed programmed cell death. This mechanism is likely to prevent the recovery of inflammatory cells and thus contributes to the resolution of inflammation.
Department of Anesthesiology and Intensive Care, University of Ulm, 89075 Ulm, Germany.
Silke
S
Schlottmann
Franziska
F
Buback
Bettina
B
Stahl
Rainer
R
Meierhenrich
Paul
P
Walter
Michael
M
Georgieff
Uwe
U
Senftleben
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli / Q000502:physiology*; D020869:Gene Expression Profiling; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha