Benznidazole blocks NF-kappaB activation but not AP-1 through inhibition of IKK.
Previously, we demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, modulates pro-inflammatory cytokines and NO release in macrophages by inhibiting NF-kappaB. We now proceeded to elucidate the molecular mechanisms by which BZL exerts its inhibitory action on NF-kappaB. 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-kappaB 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-1beta, TNF-alpha), PMA or H(2)O(2). Also, BZL delayed the activation of p38 MAPK, but not that of ERK1/2 and JNK. Finally, treatment with BZL inhibited IkappaBalpha phosporylation and hence its degradation, whereas it did not block IkappaB kinase (IKK) alpha/beta phosphorylation. Collectively, BZL behaves as a broad range specific inhibitor of NF-kappaB activation, independently of the stimuli tested.
Manarin
Romina
R
Instituto de Biología Molecular y Celular de Rosario (IBR)-CONICET, Facultad de Ciencias, Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
Pascutti
María Fernanda
MF
Ruffino
Juan Pablo
JP
De Las Heras
Beatriz
B
Boscá
Lisardo
L
Bottasso
Oscar
O
Revelli
Silvia
S
Serra
Esteban
E
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020672:I-kappa B Proteins / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009593:Nitroimidazoles; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C009999:benzonidazole