Benznidazol as a specific inhibitor of NF-kB activation pathway at different levels

MANARIN R; PASCUTTI MF; RUFINO JP; DE LAS HERAS B; BOSCA L; BOTTASSO O; REVELLI S; SERRA E

MOLECULAR IMMUNOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: London; Año: 2010 vol. 47 p. 2485 - 2491

0161-5890

Previously, we demonstrated that benznidazole(BZL), known for its antiparasitic actionon Trypanosoma cruzi, modulates pro-inflammatory cytokines and NO releas ein macrophages by inhibitingNF- B. We now proceeded to elucidate the molecular mechanisms by which BZL exerts its inhibitory actionon NF-kB. We demonstrated that the inhibitory effect of BZL is not extended to other macrophage responses, since it did not inhibit other typical hallmarks of macrophage activation such as phagocytosis, MHC-II molecules expression or production of reactive oxygen species (ROS) by NADPHoxidase. BZL was able to interfere specifically with the activation of NF-kB pathway without affecting AP-1activation in RAW264.7 macrophages, not only in LPS-mediated activation, but also for other stimuli, such as pro-inflammatory cytokines (IL-1 TNF), PMA or H2O2. Also, BZL delayed the activation of p38MAPK, but not that of  ERK1/2 andJNK. Finally, treatment with BZL inhibited IkB phosporylation and hence its degradation, whereas it did notblock IKK phosphorylation. Collectively, BZL behaves as a broad range specific inhibitor of NFk B activation, independently of the stimuli tested.