Abstract
Sepsis is a systemic response to infection in which toxins, such as bacterial lipopolysaccharide (LPS), stimulate the production of inflammatory mediators like the cytokine tumor necrosis factor alpha (TNF-alpha). Previous studies from our laboratory have revealed that LPS inhibits the intestinal absorption of L-leucine and D-fructose in rabbit when it was intravenously administered, and that TNF-alpha seems to mediate this effect on amino acid absorption. To extend this work, the present study was designed to evaluate the possible effect of TNF-alpha on D-galactose intestinal absorption, identify the intracellular mechanisms involved and establish whether this cytokine mediates possible LPS effects. Our findings indicate that TNF-alpha decreases D-galactose absorption both in rabbit intestinal tissue preparations and brush-border membrane vesicles. Western blot analysis revealed reduced amounts of the Na+/glucose cotransporter (SGLT1) protein in the plasma membrane attributable to the cytokine. On the contrary, TNF-alpha increased SGLT1 mRNA levels. Specific inhibitors of the secondary messengers PKC, PKA, the MAP kinases p38 MAP, JNK, MEK1/2 as well as the proteasome, diminished the TNF-alpha-evoked inhibitory effect. LPS inhibition of the uptake of the sugar was blocked by a TNF-alpha antagonist. In conclusion, TNF-alpha inhibits D-galactose intestinal absorption by decreasing the number of SGLT1 molecules at the enterocyte plasma membrane through a mechanism in which several protein-like kinases are involved.
(c) 2006 Wiley-Liss, Inc.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anthracenes / administration & dosage
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Anthracenes / pharmacology
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Blotting, Northern
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Blotting, Western
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Cell Membrane / drug effects
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Enzyme Inhibitors / pharmacology
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Galactose / antagonists & inhibitors*
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Imidazoles / administration & dosage
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Imidazoles / pharmacology
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Indoles / administration & dosage
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Indoles / pharmacology
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Injections, Intravenous
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Intestinal Absorption / drug effects*
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Intestinal Absorption / physiology
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / metabolism
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Intestines / drug effects*
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Male
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Maleimides / administration & dosage
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Maleimides / pharmacology
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Microvilli / drug effects
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Microvilli / metabolism
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Peptides / administration & dosage
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Peptides / pharmacology
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Proteasome Inhibitors
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase Inhibitors / pharmacology
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Pyridines / administration & dosage
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Pyridines / pharmacology
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RNA, Messenger / metabolism
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Rabbits
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Sepsis / metabolism
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Sodium-Glucose Transporter 1 / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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Anthracenes
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Enzyme Inhibitors
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Imidazoles
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Indoles
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Lipopolysaccharides
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Maleimides
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Peptides
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Proteasome Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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RNA, Messenger
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Sodium-Glucose Transporter 1
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Tumor Necrosis Factor-alpha
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pyrazolanthrone
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IP 20
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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bisindolylmaleimide I
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SB 203580
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Galactose