Activates NF-κB Signaling via Redundant Pathways.

subverts neutrophil function permitting intracellular survival, propagation and transmission. Sustained pro-inflammatory response, recruitment of new host cells for population expansion, and delayed apoptosis are associated with prolonged nuclear presence of NF-κB. We investigated NF-κB signaling and transcriptional activity with infection using inhibitors of NF-κB signaling pathways, and through silencing of signaling pathway genes. How inhibitors or silencing affected growth, inflammatory response (transcription of the κB-enhanced genes and ), and NF-κB signaling pathway gene expression were tested. Among -infected HL-60 cells, nuclear NF-κB p50, p65, and p52 were detected by immunoblots or iTRAQ proteomics. growth was affected most by the IKKαβ inhibitor wedelolactone (reductions of 96 to 99%) as compared with SC-514 that selectively inhibits IKKβ, illustrating a role for the non-canonical pathway. Wedelolactone inhibited transcription of both ( = 0.001) and ( = 0.002) in infected cells. Compared to uninfected THP-1 cells, infection led to >2-fold down regulation of 64 of 92 NF-κB signaling pathway genes, and >2-fold increased expression in only 4. Wedelolactone and SC-514 reversed downregulation in all 64 and 45, respectively, of the genes down-regulated by infection, but decreased expression in 1 gene with SC-514 only. Silencing of 20 NF-κB signal pathway genes increased bacterial growth in 12 (, and ). Most findings support canonical pathway activation; however, the presence of NFKB2 in infected cell nuclei, selective non-canonical pathway inhibitors that dampen and transcription with infection, upregulation of non-canonical pathway target genes and , enhanced bacterial growth with and silencing provide evidence for non-canonical pathway signaling. Whether this impacts distinct inflammatory processes that underlie disease, and whether and how subverts NF-κB signaling via these pathways, need to be investigated.