Effects of MK-886, an inhibitor of the 5-lipoxygenase-activating protein, on peripheral blood mononuclear cells from patients with Chagas' heart disease.

BACKGROUND: Chagas disease, caused by Trypanosoma cruzi, remains a major public health challenge in Latin America. Lipid mediators, including leukotrienes, play a key role in modulating the immune response during infection. 5-Lipoxygenase deficiency has been associated with cardioprotective effects in mouse models. Accordingly, this study evaluated the effects of MK-886, a 5-lipoxygenase-activating protein inhibitor, on the immune response of cells from patients with Chagas heart disease. METHODS: Peripheral blood mononuclear cells (PBMCs) from patients with chronic Chagas disease were stimulated with T. cruzi antigen in the presence or absence of MK-886. Cytokine production (interferon [IFN]-γ, interleukin [IL]-13, IL-17, IL-10, and tumor necrosis factor [TNF]-α), apoptosis, necrosis, and cell proliferation were assessed. RESULTS: T. cruzi antigen significantly increased cytokine production, cell death, and proliferation in PBMCs from patients with chronic Chagas disease. MK-886 significantly reduced IFN-γ, IL-13, and IL-17 production without altering IL-10 or TNF-α production. Additionally, MK-886 treatment markedly reduced apoptosis, necrosis, and proliferation in T. cruzi-stimulated PBMCs from patients with chronic Chagas disease. CONCLUSIONS: MK-886 has the potential to reduce tissue-damaging inflammation and fibrosis associated with Th1, Th2, and Th17 responses without inducing immunosuppression, while IL-10 and TNF-α production remained unchanged in PBMCs from patients with chronic Chagas disease. Accordingly, targeting the leukotriene pathway may delay the progression of cardiac damage in Chagas disease.