Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

Pediatr Res. 2017 Dec;82(6):1064-1072. doi: 10.1038/pr.2017.182. Epub 2017 Aug 23.

Abstract

BackgroundThe pro-inflammatory consequences of IL1β expression contribute to the pathogenesis of bronchopulmonary dysplasia. Selectively targeting Lipopolysaccharide (LPS)-induced IκBβ/NFκB signaling attenuates IL1β mRNA expression in macrophages. Whether targeting IκBβ/NFκB signaling affects the anti-apoptotic gene expression, a known consequence of global LPS-induced NFκB inhibition, is unknown.MethodsMacrophages (RAW 264.7, bone marrow-derived macrophage) were assessed for LPS-induced IL1β mRNA/protein expression, anti-apoptotic gene expression, cell viability (trypan blue exclusion), and activation of apoptosis (caspase-3 and PARP cleavage) following pharmacologic and genetic attenuation of IκBβ/NFκB signaling. Expressions of IL1β and anti-apoptotic genes were assessed in endotoxemic newborn mice (P0) with intact (WT), absent (IκBβ KO), and attenuated (IκBβ overexpressing) IκBβ/NFκB signaling.ResultsIn cultured macrophages, pharmacologic and genetic inhibition of LPS-induced IκBβ/NFκB signaling significantly attenuated IL1β mRNA and protein expression. Importantly, targeting IκBβ/NFκB signaling did not attenuate LPS-induced expression of anti-apoptotic genes or result in cell death. In endotoxemic neonatal mice, targeting LPS-induced IκBβ/NFκB signaling significantly attenuated pulmonary IL1β expression without affecting the anti-apoptotic gene expression.ConclusionTargeting IκBβ/NFκB signaling prevents LPS-induced IL1β expression without inducing apoptosis in cultured macrophages and in the lungs of endotoxemic newborn mice. Inhibiting this pathway may prevent inflammatory injury without affecting the protective role of NFκB activity in the developing lung.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects*
  • Cell Line
  • I-kappa B Proteins / metabolism*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Lung / cytology
  • Lung / drug effects*
  • Lung / growth & development*
  • Lung / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred ICR
  • NF-kappa B / metabolism*
  • RNA, Messenger
  • Signal Transduction / drug effects*

Substances

  • I kappa B beta protein
  • I-kappa B Proteins
  • Interleukin-1beta
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Messenger