Inhibitory effect of TNF-alpha on the intestinal absorption of galactose.
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.
Amador
P
P
Department of Pharmacology and Physiology, Physiology Unit, Veterinary Faculty, University of Zaragoza, E-50013 Zaragoza, Spain.
García-Herrera
J
J
Marca
M C
MC
de la Osada
J
J
Acín
S
S
Navarro
M A
MA
Salvador
M T
MT
Lostao
M P
MP
Rodríguez-Yoldi
M J
MJ
D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005690:Galactose / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000008:administration & dosage / Q000494:pharmacology; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D018805:Sepsis / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000873:Anthracenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D010455:Peptides; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D051269:Sodium-Glucose Transporter 1; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; C058824:IP 20; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C070515:bisindolylmaleimide I; C093642:SB 203580; D005690:Galactose