McKenna Sarah, Wright Clyde J
Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
J Cell Sci. 2015 Jun 1;128(11):2143-55. doi: 10.1242/jcs.168351. Epub 2015 Apr 23.
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.
脓毒性休克的多种介质受转录因子核因子κB（NFκB）调控。然而，完全抑制NFκB会加重病情，因此有必要评估减轻促炎反应的靶向策略。在此，我们证明，在小鼠巨噬细胞中，低剂量NFκB抑制剂可特异性减弱脂多糖（LPS）诱导的IκBβ降解以及特定靶基因子集（编码IL1β、IL6、IL12β）的表达。功能获得和功能丧失实验证明了NFκB家族成员IκBβ（也称为NFKBIB）在这些基因表达中起必要且充分的作用。此外，从过表达IκBβ的小鼠中分离出的成纤维细胞和巨噬细胞均表现出LPS诱导的IκBβ-NFκB信号传导以及IL1β、IL6和IL12β表达减弱。用含有cRel核定位序列的细胞可渗透肽预处理野生型小鼠胚胎成纤维细胞，进一步证实了IκBβ及其NFκB亚基结合伴侣cRel在LPS诱导的基因表达中的作用，该预处理减弱了IL6表达。我们证明，LPS诱导的IκBβ-NFκB信号传导可被选择性调节，以减弱特定促炎靶基因的表达，从而为遭受全身性炎症应激的患者提供治疗思路。
