title: Modulation of inflammatory response and parasitism by 15-Deoxy-Δ(12,14) prostaglandin J(2) in Trypanosoma cruzi-infected cardiomyocytes.
abstract: Trypanosoma cruzi infection produces an intense inflammatory response in diverse tissues including the heart. The inflammatory reaction is critical for the control of the parasites' proliferation and evolution of Chagas disease. 15-Deoxy-Δ(12,14) prostaglandin J(2) (15dPGJ2) can repress the inflammatory response in many experimental models. However, the precise role of peroxisome proliferator-activated receptor γ (PPARγ) ligands in T. cruzi infection or in Chagas disease is poorly understood. This work reports the first evidence that 15dPGJ2 treatment increases the number of intracellular parasites as shown by fluorescence microscopy and it is also able to inhibit the expression and activity of different inflammatory enzymes such as inducible nitric oxide synthase (NOS-2), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), as well as pro-inflammatory cytokine (TNF-α and IL-6) mRNA expression in neonatal mouse cardiomyocytes after T. cruzi infection. Transfection of cardiomyocytes with small interfering RNA (siRNA) induces silencing of PPARγ and impairs the effects of 15dPGJ2 on the modulation of pro-inflammatory enzymes. Moreover, transfection restores the ability of these cells to control the intracellular growth of T. cruzi. We also found that PPARγ-independent pathways are involved, since 15dPGJ2 also exerts its effect through extracellular signal-regulated kinases-mitogen-activated protein kinase (Erk-MAPK) and nuclear factor-κB (NF-κB). The use of specific pharmacological inhibitors confirmed these findings. Our data point out that 15dPGJ2 is a potent modulator of the inflammatory process and regulator of parasites growth through PPARγ-dependent and independent (Erk-MAPK- and NF-κB) pathways in T. cruzi infected neonatal cardiac cells.
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos (CEFYBO-CONICET-UBA), Buenos Aires, Argentina.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Hovsepian
authors.forename: Gerardo A
authors.initials: GA
authors.lastname: Mirkin
authors.forename: Federico
authors.initials: F
authors.lastname: Penas
authors.forename: Anna
authors.initials: A
authors.lastname: Manzano
authors.forename: Ramon
authors.initials: R
authors.lastname: Bartrons
authors.forename: Nora B
authors.initials: NB
authors.lastname: Goren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000469:parasitology; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000276:immunology / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D047495:PPAR gamma; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2