Up-regulation in endothelin-1 by Helicobacter pylori lipopolysaccharide interferes with gastric mucin synthesis via epidermal growth factor receptor transactivation.
OBJECTIVE
Endothelin-1 (ET-1), a key mediator of inflammatory processes associated with bacterial infection, is a 21-amino acid peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1) that acts through G protein-coupled ET(A) and ET(B) receptors. Here we report on the role of ET-1 in the mediation of the detrimental influence of Helicobacter pylori on the synthesis of gastric mucin.


METHODS
Rat gastric mucosal cells were exposed to H. pylori key virulence factor, lipopolysaccharide (LPS).


RESULTS
The LPS inhibitory effect on gastric mucin synthesis was accompanied by a marked increase in ET-1 generation and enhancement in ECE-1 activity. Inhibition of ECE-1 with phosphoramidon not only led to the impedance of LPS-induced ET-1 generation, but also countered the detrimental effect of LPS on mucin synthesis. Moreover, the LPS inhibitory effect on mucin synthesis was blocked by ET(A) receptor antagonist BQ610, but not by ET(B) receptor antagonist BQ788. Furthermore, the LPS-induced suppression in gastric mucin synthesis was countered in a concentration-dependent fashion by PD153035 (81.7%), a specific inhibitor of epidermal growth factor receptor (EGFR) kinase as well as PP2 (69.8%), a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR transactivation.


CONCLUSIONS
Our findings are the first to show that the detrimental effect of H. pylori on gastric mucin synthesis is intimately linked to the events associated with ECE-1 up-regulation, enhancement in ET-1 production, and G protein-coupled ET(A) receptor activation that triggers the EGFR transactivation.
Slomiany
Bronislaw L
BL
Research Center, C875, UMDJN-NJ Dental School, 110 Bergen Street, P.O. Box 1709, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005752:Gastric Mucins / Q000096:biosynthesis* / Q000187:drug effects; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D016480:Helicobacter pylori; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005752:Gastric Mucins; D008070:Lipopolysaccharides; D011799:Quinazolines; D066246:ErbB Receptors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline