Response to Trypanosoma cruzi by Human Blood Cells Enriched with Dentritic Cells Is Controlled by Cyclooxygenase-2 Pathway

Abstract

Chagas disease (Cd) or American human trypanosomiasis is caused by Trypanosoma cruzi and affects ~7 million people, mostly in Latin America. The infective trypomastigote forms of the parasite can invade several human blood cell populations, including monocytes and dendritic cells (DC). Although these cells display a wide functional diversity, their interactions with T. cruzi via cyclooxygenase (COX) and cyclic adenosine monophosphate (cAMP) dependent pathways have not been analyzed. To exploiting this mechanism, DC-enriched peripheral human blood mononuclear cell populations (DC-PBMC) were used as our model. Our results showed that the treatment of these cell populations with celecoxib (CEL), a cyclooxygenase-2 selective inhibitor or SQ 22,536, an adenilate cyclase inhibitor, significantly caused marked inhibition of T. cruzi infection. In contrast, aspirin (ASA, a non-selective COX-1 and COX-2 inhibitor) treatment did not inhibit the infection of the cells by the parasite and was independent of nitric oxide (NO) production. The expression of co-stimulatory molecules CD80 and CD86 were similar on cells treated or not with both COX-inhibitors. The infection stimulated the release of TNF-α, IL-1β, IL-6, IL-8, and IL-10 production by infected cells. Treatment with ASA or CEL did not affect TNF-α, IL-6, IL-8, IL-10, and NO production by infected cells, but increased IL-1β production by them. Our results suggest a key role of COX-2 and cAMP pathways in T. cruzi invasion process of human blood cells and these pathways may represent targets of new therapeutic options for Cd.

Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

“…Therefore, the role of COX-2 during T. gondii infection is PGE 2 -dependent. Our findings are in agreement with Lonien et al (2017). Human dendritic cells infected by T. cruzi and treated with celecoxib plus PGE 2 presented increased internalization of trypomastigotes in comparison to cells treated with only celecoxib, indicating that PGE 2 inhibition using celecoxib was reverted and restored the invasion of the parasite in the host cells (Lonien et al, 2017).…”

“…Our findings are in agreement with Lonien et al (2017). Human dendritic cells infected by T. cruzi and treated with celecoxib plus PGE 2 presented increased internalization of trypomastigotes in comparison to cells treated with only celecoxib, indicating that PGE 2 inhibition using celecoxib was reverted and restored the invasion of the parasite in the host cells (Lonien et al, 2017). Also, our previous study showed that human trophoblast cells treated with PGE 2 presented higher susceptibility to T. gondii infection (RH strain), evidencing that PGE 2 can facilitate parasite proliferation (Barbosa et al, 2014).…”

“…Additionally, a study has demonstrated that curcumin, a natural product isolated from Curcuma longa L. (Zingiberaceae), enhanced survival and provoked a relevant inflammatory response in the heart of mice infected with T. cruzi , since curcumin was able to block COX-2 induction and PGE 2 release (Hernández et al, 2016). A recently published study showed that celecoxib significantly inhibited T. cruzi infection in dendritic cell-enriched peripheral human blood mononuclear cell populations, but aspirin, a non-selective COX-1 and COX-2 inhibitor, did not present the same effect (Lonien et al, 2017). The effect of celecoxib in reducing the T. cruzi invasion in human dendritic cells was dose-dependent (Lonien et al, 2017), according to our findings in C. calomys peritoneal macrophages.…”

“…A recently published study showed that celecoxib significantly inhibited T. cruzi infection in dendritic cell-enriched peripheral human blood mononuclear cell populations, but aspirin, a non-selective COX-1 and COX-2 inhibitor, did not present the same effect (Lonien et al, 2017). The effect of celecoxib in reducing the T. cruzi invasion in human dendritic cells was dose-dependent (Lonien et al, 2017), according to our findings in C. calomys peritoneal macrophages. Previous studies also demonstrated association between PGE 2 /COX-2 axis and susceptibility to Leishmania protozoa.…”

Efeitos de terapêutica antiplaquetária e vasodilatadora microcirculatória sobre os distúrbios microvasculares e sintomas anginosos que ocorrem na cardiopatia crônica da doença de Chagas. Estudo prospectivo com coronariografia e cintilografia miocárdica de perfusão

“…Além disso, outros trabalhos associaram o uso de AAS a atividade antiinflamatória concomitante ao aumento de produção de IL-1 e NO por macrófagos, apontando o envolvimento das lipoxinas, prostaglandina e NO, elementos alternativos à inibição da COX, na regulação da ação anti-T. cruzi por essas células (Hideko Tatakihara et al, 2007;Molina-Berrios et al, 2013;Malvezi et al, 2014;Lonien et al, 2017).…”