Central role of extracellular signal-regulated kinase and Toll-like receptor 4 in IL-10 production in regulatory dendritic cells induced by Trypanosoma cruzi

PONCINI CV; GIMENEZ G; PONTILLO CA; ALBA-SOTO, CD; DE ISOLA, ELD; PIAZZON I; GONZÁLEZ CAPPA, SM

MOLECULAR IMMUNOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2010 vol. 47 p. 1981 - 1988

0161-5890

a b s t r a c tSeveral Trypanosoma cruzi molecules that stimulate macrophages activity were described as Toll-likereceptor 2 (TLR2) ligands. Besides, the models of dendritic cells (DC) are poorly characterised. We havepreviously demonstrated that live-trypomastigotes (Tp) plus lipopolysaccharide (LPS) induce DC withtolerogenic properties that produce high levels of interleukin (IL)-10 and an impaired capacity to inducelymphoproliferation. Here, we show that the regulatory phenotype was observed with heat-killed trypomastigotes(Tphk) stimulation, ruling out DC infection. T. cruzi induced a particular DC activation stateincreasing LPS-activation of extracellular regulated kinase (ERK) 1/2 and signal transducer and activatorof transcription (STAT) 3. Inhibition of ERK down-regulated IL-10 production and restored DC stimulatorycapacity, showing the importance of this pathway in the DC modulation. A recent work shows thatsignalling via TLR4 and TLR2 induces a synergism in anti-inflammatory cytokine production in murineDC. Upon TLR2 and TLR4 stimulation using Pam3Cys or LPS and Tphk in DC from TLR2 knock out (KO) orTLR4-mutant mice, we showed that high levels of IL-10 were independent of TLR2 but associated withTLR4 and NF-B signallization. Although sialic acid has been described as a molecule responsible of DCinhibition, we determine that it is not associated with T. cruzi-IL-10 modulatory response. In conclusion,all these findings demonstrate a key role of ERK and TLR4 in association with NF-B in IL-10 modulationinduced by T. cruzi and suggest that this regulatory effect involves parasite–DC interactions not describedyet.© 2010 Published by Elsevier Ltd.