Journal article
Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-kappa B Activation in Macrophages
Molecular and cellular biology, Vol.30(17), pp.4354-4366
09/01/2010
DOI: 10.1128/MCB.00069-10
PMCID: PMC2937543
PMID: 20584979
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(Delta myel) mice) show enhanced susceptibility to lipopolysaccharide (LPS)-induced septic shock accompanied by exaggerated liver failure. Furthermore, primary macrophages derived from PDK-1(Delta myel) mice lack LPS- and Pam3CSK4-stimulated AKT activity but exhibit increased mRNA expression and release of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Moreover, LPS- and Pam3CSK4-stimulated primary macrophages exhibit enhanced phosphorylation and degradation of I kappa B alpha. 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(Delta 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-kappa B activation in macrophages in vivo.
Details
- Title: Subtitle
- Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-kappa B Activation in Macrophages
- Creators
- Bhagirath Chaurasia - University of CologneJan Mauer - University of CologneLinda Koch - University of CologneJulia Goldau - University of CologneAnja-Sterner Kock - University of CologneJens C. Bruening - University of Cologne
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.30(17), pp.4354-4366
- Publisher
- Amer Soc Microbiology
- DOI
- 10.1128/MCB.00069-10
- PMID
- 20584979
- PMCID
- PMC2937543
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Number of pages
- 13
- Grant note
- SFB 670; DFG Br 1492-7/4 / International Graduate School of Genomics and Functional Genomics, Cologne, Germany
- Language
- English
- Date published
- 09/01/2010
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359946102771
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