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

We have shown previously that phenol/water extracts derived from two novel Treponema species, Treponema maltophilum, and Treponema brennaborense, rese mbling lipoteichoic acid (LTA), induce cytokines in mononuclear cells. This response was lipopolysaccharide binding-protein (LBP)-dependent and involv ed Toll-like receptors (TLRs), Here we show that secretion of tumor necrosi s factor-alpha induced by Treponema culture supernatants and extracted LTA was paralleled by an LBP-dependent phosphorylation of mitogen-activated pro tein 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-cu leve ls were significantly reduced by addition of inhibitors of p42/44 and p38, PD 98059 and SE 203580, respectively. Treponeme LTA differed from bacterial lipopolysaccharide regarding time course of p42/44 phosphorylation, exhibi ting a prolonged activation of MAPKs. Furthermore, MAPK activation and cyto kine induction failed to be strictly correlated. Involvement of TLR-4 for p hosphorylation of p42/44 was shown employing the neutralizing anti-murine T LR-4 antibody MTS 510, In TLR-2-negative U373 cells, the compounds studied differed regarding MAPK activation with T. maltophilum leading to a stronge r activation, In summary, the data presented here show that treponeme LTA a re able to activate the MAPK and stress-activated protein kinase pathway in volving LBP and TLR-4.