THE JNK INHIBITOR SP600125 INDUCES p38 ACTIVATION AND INCREASES TRYPANOSOMA CRUZI GROWTH IN MACROPHAGES BY CHANGING THE BALANCE OF iNOS AND ARGINASE ACTIVITIES. SIMILAR EFFECTS ARE PRODUCED BY CRUZIPAIN.

STEMPIN, CC. GARRIDO, VV. DULGERIAN, LR. CERBÁN, FM.

INTERNATIONAL JOURNAL FOR PARASITOLOGY

Elsevier (Manuscrito en Revision).

Lugar: Marrickville, Australia; Año: 2006

0020-7519

ABSTRACT Cruzipain (Cz), an antigen of Trypanosoma cruzi, mediates the activation of arginase involving p38 MAPK. In this work, it was studied whether the phosphorylation of MAPKs into macrophages (Mf) could be induced by Cz and/or by the parasite. We found that Cz induced activation of p38, while the parasite produced phosphorylation of JNK and p44/p42. MAPK phosphorylation changed and JNK activation was blocked when Mf were pre-incubated with Cz, before coming into contact with T. cruzi. We investigated the role of JNK inhibitor SP600125 on T. cruzi infection, since it also induces p38 phosphorylation. Thus, J774 cells were pre-treated with SP600125 and then infected with T. cruzi. This set of cells showed a decrease in nitric oxide (NO) production and an increase in arginase I expression. Another group of J774 cells was pre-treated with SP600125 and incubated with Cz before being infected with T. cruzi. This second group showed a greater reduction in NO production. These results can also be correlated with the parasitic growth, since SP600125 favors parasite proliferation in infected Mf. The ex-vivo treatment with SP600125 on adherent spleen cells (ASC) of BALB/c infected mice also increased the number of intracellular parasites. This is the first time the impact of SP600125 on the parasite infection has been demonstrated. Our results also show that JNK pathway is able to control T. cruzi growth in the Mf. In addition, Cz could be involved in the survival of T. cruzi in the Mf by changing the MAPK phosphorylation.