RESUMO
To date, the implications of prostaglandin I2 (PGI2), a prominent lipid mediator for modulation of immune responses, has not been clearly understood in Brucella infection. In this study, we found that cyclooxygenase-2 (COX-2) was significantly expressed in both infected bone marrow-derived macrophages (BMMs) and RAW 264.7 cells. Prostaglandin I2 synthase (PTGIS) expression was not significantly changed, and PGI2receptor (PTGIR) expression was downregulated in BMMs but upregulated in RAW 264.7 macrophages at late infection. Here, we presented that PGI2, a COX-derived metabolite, was produced by macrophages during Brucella infection and its production was regulated by COX-2 and IL-10. We suggested that PGI2 and selexipag, a potent PGI2 analogue, inhibited Brucella internalization through IP signaling which led to down-regulation of F-actin polymerization and p38α MAPK activity. Administration with selexipag suppressed immune responses and resulted in a notable reduction in bacterial burden in spleen of Brucella-challenged mice. Taken together, our study is the first to characterize PGI2 synthesis and its effect in evasion strategy of macrophages against Brucella infection.
Assuntos
Brucella abortus/imunologia , Brucelose/tratamento farmacológico , Epoprostenol/administração & dosagem , Macrófagos/imunologia , Receptores de Epoprostenol/agonistas , Acetamidas/administração & dosagem , Animais , Brucelose/imunologia , Brucelose/microbiologia , Ciclo-Oxigenase 2/metabolismo , Sistema Enzimático do Citocromo P-450 , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Pirazinas/administração & dosagem , Células RAW 264.7 , Receptores de Epoprostenol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Organismos Livres de Patógenos EspecíficosRESUMO
In this study, we investigated the effects of gallic acid (GA) in intracellular signaling within murine macrophages and its contribution to host immunity during Brucella infection. In vitro analysis revealed that GA treatment decreased F-actin content and suppressed p38α phosphorylation level. In vivo analysis showed that GA treatment reduced inflammation and proliferation of Brucella in spleens of mice in comparison to PBS treatment yielding a significant protection unit. For the analysis of immune response, the uninfected GA-treated mice showed increased production of IFN-γ and MCP-1, and the Brucella-infected GA-treated mice showed elevated levels of IL-12p70, TNF, IFN-γ, MCP-1, IL-10 and IL-6 in comparison to negative and positive control groups, respectively. These findings demonstrate the therapeutic effects of GA against Brucella infection through interference on intracellular signaling pathway, induction of cytokine production and protection from bacterial proliferation in spleens of mice.