Benznidazole blocks NF-kB activation but not AP-1 through inhibition of IKK

MANARIN, ROMINA; PASCUTTI, FERNANDA; RUFFINO JUAN PABLO; DE LAS HERAS, B; BOSCA, L; BOTTTASSO O; REVELLI S; SERRA ESTEBAN

MOLECULAR IMMUNOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

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

0161-5890

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:ES-MX; mso-fareast-language:ES-MX;} span.shorttext {mso-style-name:short_text; mso-style-unhide:no;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Previously, we demonstrated that Benznidazole (BZL), known for its antiparasitic action on T. cruzi, modulates pro-inflammatory cytokines and NO release in macrophages by inhibiting NF-κB. We now proceeded to elucidate the molecular mechanisms by which BZL exerts its inhibitory action on 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 NADPH oxidase. BZL was able to interfere specifically with the activation of NF-kB pathway without affecting AP-1 activation in RAW 264.7 macrophages, not only in LPS-mediated activation, but also for other stimuli, such as pro-inflammatory cytokines (IL-1b, TNF-a), PMA or H2O2. Also, BZL delayed the activation of p38 MAPK, but not that of ERK1/2 and JNK. Finally, treatment with BZL inhibited IkBa phosporylation and hence its degradation, whereas it did not block IkB Kinase (IKK) a/b phosphorylation. Collectively, BZL behaves as a broad range specific inhibitor of NF-kB activation, independently of the stimuli tested.