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Inhibiting I?B?-NF?B signaling attenuates the expression of select pro-inflammatory genes.

ABSTRACT: Multiple mediators of septic shock are regulated by the transcription factor nuclear factor ?B (NF?B). However, complete NF?B inhibition can exacerbate disease, necessitating evaluation of targeted strategies to attenuate the pro-inflammatory response. Here, we demonstrate that in murine macrophages, low-dose NF?B inhibitors specifically attenuates lipopolysaccharide (LPS)-induced I?B? degradation and the expression of a select subset of target genes (encoding IL1?, IL6, IL12?). Gain- and loss-of-function experiments demonstrate the necessary and sufficient role of inhibitor of NF?B family member I?B? (also known as NFKBIB) in the expression of these genes. Furthermore, both fibroblasts and macrophages isolated from I?B? overexpressing mice demonstrate attenuated LPS-induced I?B?-NF?B signaling and IL1?, IL6 and IL12? expression. Further confirming the role of I?B? and its NF?B 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 I?B?-NF?B 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.

SUBMITTER: McKenna S

PROVIDER: S-EPMC4457027 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

McKenna Sarah S Wright Clyde J CJ

Journal of cell science 20150423 11

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-o ...[more]

PMID: 25908863

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Inhibiting I?B?-NF?B signaling attenuates the expression of select pro-inflammatory genes.

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

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