Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-kB Activation in Macrophages

  • Chaurasia B
  • Mauer J
  • Koch L
 et al. 
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Abstract

Phosphoinositide-dependent kinase 1 (PDK-1) represents an important signaling component in the phosphatidylinositol 3-kinase (PI3K) pathway, which plays an essential role in controlling a coordinated innate immune response. Here, we show that mice with conditional disruption of PDK-1 specifically in myeloid lineage cells (PDK-1+�myel mice) show enhanced susceptibility to lipopolysaccharide (LPS)-induced septic shock accompanied by exaggerated liver failure. Furthermore, primary macrophages derived from PDK-1+�myel mice lack LPS- and Pam3CSK4-stimulated AKT activity but exhibit increased mRNA expression and release of tumor necrosis factor alpha (TNF-+�) and interleukin 6 (IL-6). Moreover, LPS- and Pam3CSK4-stimulated primary macrophages exhibit enhanced phosphorylation and degradation of I+�B+�. While immediate upstream Toll-like receptor 4 (TLR-4)-induced signaling, including IL-1 receptor (IL-1R)-associated protein kinase (IRAK) phosphorylation, is unaltered in the absence of PDK-1, macrophages from PDK-1+�myel mice exhibit prolonged ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF-6) in response to LPS stimulation. These experiments reveal a novel PDK-1-dependent negative feedback inhibition of TLR-induced NF-+�B activation in macrophages in vivo

Author-supplied keywords

  • FACTOR-ALPHA
  • IL-1
  • IRAK
  • Il-6
  • Immune
  • Immune response
  • Interleukin-6
  • LPS
  • Lipopolysaccharide
  • Liver
  • Macrophage
  • Macrophages
  • Mice
  • NF+�B
  • NF-kB
  • Protein
  • SEPTIC SHOCK
  • Signaling
  • TLR4
  • TNF-�
  • TRAF6
  • Toll-Like Receptor 4
  • Toll-like receptor
  • Tumor Necrosis Factor
  • activation
  • activity
  • cells
  • expression
  • factor
  • in vivo
  • inhibition
  • interleukin
  • kinase
  • mRNA
  • phosphorylation
  • receptor
  • stimulation
  • ubiquitination

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Authors

  • Bhagirath Chaurasia

  • Jan Mauer

  • Linda Koch

  • Julia Goldau

  • Anja Sterner Kock

  • Jens C Br++ning

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