Endosomal Accumulation of Toll-Like Receptor 4 Causes Constitutive Secretion of Cytokines and Activation of Signal Transducers and Activators of Transcription in Niemann–Pick Disease Type C (NPC) Fibroblasts: A Potential Basis for Glial Cell Activation in the NPC Brain
Mice, Knockout
0301 basic medicine
Interleukin-6
Interleukin-8
Longevity
Brain
Niemann-Pick Disease, Type C
Endosomes
Interferon-beta
Fibroblasts
Culture Media
Toll-Like Receptor 4
Mice
STAT Transcription Factors
03 medical and health sciences
Animals
Cytokines
Humans
Neuroglia
Cells, Cultured
DOI:
10.1523/jneurosci.5282-06.2007
Publication Date:
2007-02-21T18:59:09Z
AUTHORS (12)
ABSTRACT
Niemann–Pick disease type C (NPC) is an inherited lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function either protein results the endosomal accumulation cholesterol and other lipids, progressive neurodegeneration, robust glial cell activation. Here, we report that cultured human NPC fibroblasts secrete interferon-β, interleukin-6 (IL-6), IL-8, contain increased levels signal transducers activators transcription (STATs). These cells also contained Toll-like receptor 4 (TLR4) accumulated cholesterol-enriched endosomes/lysosomes, small interfering RNA knockdown this reduced cytokine secretion. In −/− mouse brain, expressed TLR4 IL-6, whereas both neuronal STATs. Genetic deletion mice IL-6 secretion but failed to alter STAT activation brain. contrast, genetic normalized suppressed findings indicate constitutive leads STATs partly TLR4. suggest similar signaling events may underlie
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