Activation of mitogen-activated protein kinases p42/44, p38, and stress-activated protein kinases in myelo-monocytic cells by Treponema lipoteichoic acid

• Published in: The Journal of biological chemistry 2001-03, Vol.276 (13), p.9713-9719
• Main Authors: Schröder, N W, Pfeil, D, Opitz, B, Michelsen, K S, Amberger, J, Zähringer, U, Göbel, U B, Schumann, R R
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - metabolism; c-Jun N-terminal kinase; Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Humans; Imidazoles - pharmacology; Immunoblotting; Interleukin-6 - metabolism; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; lipoteichoic acid; Macrophages; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Monocytes - metabolism; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Phosphotyrosine - metabolism; Pyridines - pharmacology; Teichoic Acids - metabolism; Teichoic Acids - pharmacology; Time Factors; Treponema; Treponema - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M008954200

We have shown previously that phenol/water extracts derived from two novel Treponema species, Treponema maltophilum, and Treponema brennaborense, resembling lipoteichoic acid (LTA), induce cytokines in mononuclear cells. This response was lipopolysaccharide binding-protein (LBP)-dependent and involved Toll-like receptors (TLRs). Here we show that secretion of tumor necrosis factor-alpha induced by Treponema culture supernatants and extracted LTA was paralleled by an LBP-dependent phosphorylation of mitogen-activated protein kinases (MAPKs) p42 and p44, and p38, as well as the stress-activated protein kinases c-Jun N-terminal kinases 1 and 2. Phosphorylation of p42/44 correlated with an increase of activity, and tumor necrosis factor-alpha levels were significantly reduced by addition of inhibitors of p42/44 and p38, PD 98059 and SB 203580, respectively. Treponeme LTA differed from bacterial lipopolysaccharide regarding time course of p42/44 phosphorylation, exhibiting a prolonged activation of MAPKs. Furthermore, MAPK activation and cytokine induction failed to be strictly correlated. Involvement of TLR-4 for phosphorylation of p42/44 was shown employing the neutralizing anti-murine TLR-4 antibody MTS 510. In TLR-2-negative U373 cells, the compounds studied differed regarding MAPK activation with T. maltophilum leading to a stronger activation. In summary, the data presented here show that treponeme LTA are able to activate the MAPK and stress-activated protein kinase pathway involving LBP and TLR-4.