Abstract
Inflammation plays an important pathogenic role in a number of metabolic diseases such as obesity, type 2 diabetes, and atherosclerosis. The activation of inflammation in these diseases depends at least in part on the combined actions of TLR4 signaling and endoplasmic reticulum stress, which by acting in concert can boost the inflammatory response. Defining the mechanisms involved in this phenomenon may unveil potential targets for the treatment of metabolic/inflammatory diseases. Here we used LPS to induce endoplasmic reticulum stress in the human monocyte cell-line, THP-1. The unfolded protein response, produced after LPS, was dependent on CD14 activity but not on RNA-dependent protein kinase and could be inhibited by an exogenous chemical chaperone. The induction of the endoplasmic reticulum resident chaperones, GRP94 and GRP78, by LPS was of a much lower magnitude than the effect of LPS on TLR4 and MD-2 expression. In face of this apparent insufficiency of chaperone expression, we induced the expression of GRP94 and GRP78 by glucose deprivation. This approach completely reverted endoplasmic reticulum stress. The inhibition of either GRP94 or GRP78 with siRNA was sufficient to rescue the protective effect of glucose deprivation on LPS-induced endoplasmic reticulum stress. Thus, insufficient LPS-induced chaperone expression links TLR4 signaling to endoplasmic reticulum stress.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Animals
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Cell Line
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects
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Endoplasmic Reticulum Stress / physiology*
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Glucose / pharmacology
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / metabolism
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Immunoblotting
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Lipopolysaccharide Receptors / metabolism
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Lipopolysaccharides / pharmacology
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Lymphocyte Antigen 96 / metabolism
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism*
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / metabolism
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Phosphorylation / drug effects
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RNA Interference
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Toll-Like Receptor 4 / metabolism*
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Transcription Factors / metabolism
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Unfolded Protein Response / drug effects
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Unfolded Protein Response / physiology
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eIF-2 Kinase / deficiency
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism
Substances
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DNA-Binding Proteins
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Elf2 protein, mouse
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Endoplasmic Reticulum Chaperone BiP
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HSP70 Heat-Shock Proteins
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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LY96 protein, human
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Lymphocyte Antigen 96
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Membrane Proteins
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Molecular Chaperones
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TLR4 protein, human
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Toll-Like Receptor 4
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Transcription Factors
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glucose-regulated proteins
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PERK kinase
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eIF-2 Kinase
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Glucose