Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes

Abstract

Multiple mediators of septic shock are regulated by the transcription factor nuclear factor κB (NFκB). However, complete NFκB inhibition can exacerbate disease, necessitating evaluation of targeted strategies to attenuate the pro-inflammatory response. Here, we demonstrate that in murine macrophages, low-dose NFκB inhibitors specifically attenuates lipopolysaccharide (LPS)-induced IκBβ degradation and the expression of a select subset of target genes (encoding IL1β, IL6, IL12β). Gain-and loss-of-function experiments demonstrate the necessary and sufficient role of inhibitor of NFκB family member IκBβ (also known as NFKBIB) in the expression of these genes. Furthermore, both fibroblasts and macrophages isolated from IκBβ overexpressing mice demonstrate attenuated LPS-induced IκBβ-NFκB signaling and IL1β, IL6 and IL12β expression. Further confirming the role of IκBβ and its NFκB subunit binding partner cRel in LPS-induced gene expression, pre-treatment of wild-type mouse embryonic fibroblasts with a cell-permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression. We prove that LPS-induced IκBβ-NFκB signaling can be selectively modulated to attenuate the expression of select pro-inflammatory target genes, thus providing therapeutic insights for patients exposed to systemic inflammatory stress.

Circadian clock protein Rev-erbα regulates neuroinflammation

“…2A). Of note, Nfkbib encodes the NF-κB pathway inhibitor IκBβ (29). We next examined basal and lipopolysaccharide (LPS)-induced p65 nuclear translocation in primary WT and RKO microglia.…”

“…Interestingly, Rev-erbα also binds to the Nfkbib promoter, but Rev-erbα deletion leads to decreased Nfkbib expression, suggesting that Rev-erbα binding may either act to somehow positively regulate Nfkbib transcription, or that the direct binding effects of Rev-erbα at the Nfkbib locus are minor and are counteracted by some indirect effect. Since Nfkbib acts as an inhibitor of NF-κB activation (29), loss of Nfkbib expression in Rev-erbα −/− cells could also promote inflammation. In macrophages, Rev-erbα/β integrate transcriptional signals from multiple damage-associated transcription factors, including NF-κB, Nrf2, and Smad3 (46), suggesting complex transcriptional regulation programs beyond canonical NF-κB signaling.…”

CpG‐ODN‐mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBβ to drive IL1α and IL1β expression

“…Each isoform uniquely contributes to the degree and duration of NFκB activation, as well as the NFκB transcriptome. Multiple studies have implicated IκBβ in TLR4‐mediated IL1β expression 78–80,90,91 . However, this is the first report linking IκBβ to IL1 expression following CpG‐ODN TLR9‐mediated innate immune signalling.…”

Modulation of mitogen-activated protein kinase attenuates sepsis-induced acute lung injury in acute respiratory distress syndrome rats

“…MAPKs also have an important role in inducing cytokine production. It has been previously established that inflammatory stimuli may lead to the activation of MAPK and the transcription factor NF-κB, which mediates the expression of several pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 which have an important role in many inflammatory disease processes (34)(35)(36)(37). Previous studies indicated that p38 MAPK inhibitors can suppress IL-6 and TNF-α expression in monocytes and mast cells (38,39).…”