title: IL-10 inhibits the NF-κB and ERK/MAPK-mediated production of pro-inflammatory mediators by up-regulation of SOCS-3 in Trypanosoma cruzi-infected cardiomyocytes.
abstract: Trypanosoma cruzi (T. cruzi) infection produces an intense inflammatory response which is critical for the control of the evolution of Chagas' disease. Interleukin (IL)-10 is one of the most important anti-inflammatory cytokines identified as modulator of the inflammatory reaction. This work shows that exogenous addition of IL-10 inhibited ERK1/2 and NF-κB activation and reduced inducible nitric oxide synthase (NOS2), metalloprotease (MMP) -9 and MMP-2 expression and activities, as well as tumour necrosis factor (TNF)-α and interleukin (IL)-6 expression, in T. cruzi-infected cardiomyocytes. We found that T. cruzi and IL-10 promote STAT3 phosphorylation and up-regulate the expression of suppressor of cytokine signalling (SOCS)-3 thereby preventing NF-κB nuclear translocation and ERK1/2 phosphorylation. Specific knockdown of SOCS-3 by small interfering RNA (siRNA) impeded the IL-10-mediated inhibition of NF-κB and ERK1/2 activation. As a result, the levels of studied pro-inflammatory mediators were restored in infected cardiomyocytes. Our study reports the first evidence that T. cruzi up- regulates SOCS-3 expression and highlights the relevance of IL-10 in the modulation of pro-inflammatory response of cardiomyocytes in Chagas' disease.
authors.affiliation: Instituto de Microbiología y Parasitología Médica (IMPaM, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Hovsepian
authors.forename: Federico
authors.initials: F
authors.lastname: Penas
authors.forename: Sofía
authors.initials: S
authors.lastname: Siffo
authors.forename: Gerardo A
authors.initials: GA
authors.lastname: Mirkin
authors.forename: Nora B
authors.initials: NB
authors.lastname: Goren
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016753:Interleukin-10 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000472:pathogenicity*
chemical_list: D016328:NF-kappa B; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D019950:Mitogen-Activated Protein Kinase 1