title: TNF-alpha induction by Pseudomonas aeruginosa lipopolysaccharide or slime-glycolipoprotein in human monocytes is regulated at the level of Mitogen-activated Protein Kinase activity: a distinct role of Toll-like receptor 2 and 4.
abstract: TNF-alpha production has a central role in the development and progression of Pseudomonas aeruginosa septic shock. We have previously shown that P. aeruginosa slime-glycolipoprotein (slime-GLP) is the most potent stimulant compared to P. aeruginosa lipopolysaccharide (LPS), for TNF-alpha production and NF-kB activation in human monocytes. Herein, we show that secretion of TNF-alpha by fresh human monocytes, induced by P. aeruginosa slime-GLP, LPS or viable bacteria, was paralleled by phosphorylation and/or activation of Mitogen-activated Protein Kinases (MAPKs) ERK1/2, p38 as well as c-Jun NH(2)-terminal kinase. TNF-alpha levels were significantly reduced by ERK1/2 inhibitor (PD98059), or p38 inhibitor (SB203580). Combination of both inhibitors almost abolished TNF-alpha induction. Pseudomonas aeruginosa slime-GLP differed from the P. aeruginosa-LPS only regarding the strength of p38 and ERK1/2 activation, with slime-GLP leading to a stronger activation of p38 and ERK1/2. Involvement of TLR2 and TLR4 for phosphorylation of p38 and ERK1/2 was shown using specific blocking anti-TLR2 and anti-TLR4 antibodies. Activation of both p38 and ERK1/2 induced by P. aeruginosa slime-GLP was dramatically reduced in the presence of anti-TLR2 and to a lesser degree in the presence of anti-TLR4, whereas the P. aeruginosa-LPS-induced stimulation was inhibited only in the presence of anti-TLR4. Our data show that P. aeruginosa viable bacteria, through slime-GLP, stimulate specific members of the MAPKs more efficiently than the P. aeruginosa-LPS, involving mainly TLR2.
authors: Department of Microbiology, School of Medicine, University of Patras, Patras, Greece.
authors: G
authors: G
authors: Lagoumintzis
authors: P
authors: P
authors: Xaplanteri
authors: G
authors: G
authors: Dimitracopoulos
authors: F
authors: F
authors: Paliogianni
mesh_terms: D001426:Bacterial Proteins / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D011725:Pyridines / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D005419:Flavonoids; D007093:Imidazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C025431:extracellular slime proteins, bacterial; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one