Inhibitory effect of PGE₂ on the killing of Paracoccidioides brasiliensis by human monocytes can be reversed by cellular activation with cytokines

Abstract

Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, a deep mycosis endemic in Latin America. Studies to elucidate the host–parasite relationship in this mycosis have demonstrated that non-activated phagocytes fail to kill the etiologic agent. Investigations of human monocytes have shown that the lack of fungicidal activity is partially associated with the capacity of a high-virulence strain to induce PGE₂ release by these cells. This eicosanoid inhibits production of TNF-α, the cytokine involved in cell activation for release of H₂O₂, the fungicidal metabolite. Cell priming with IFN-γ was shown to partially reverse this inhibitory effect. In this study, we asked whether monocyte challenge with a low-virulence strain of this fungus would also result in PGE₂ release and consequently inhibition of antifungal activities. We also assessed whether PGE_2, besides inhibiting production of TNF-α, a monocyte-activating cytokine, also affects IL-10. The latter, in contrast to TNF-α is a monocyte-suppressing cytokine. Finally, we evaluated whether priming cells with other cytokines, namely TNF-α and GM-CSF, could be more effective than IFN-γ in reversing the PGE₂ inhibitory effect. The results revealed that the less virulent P. brasiliensis strain also induces human monocytes to release PGE₂. However, the inhibitory effect of PGE₂ was less pronounced when cells were challenged with this strain than with the more virulent one. It was also demonstrated that PGE₂, while inhibits TNF-α production, tends to increase IL-10 levels. Priming with GM-CSF or TNF-α was more effective than IFN-γ in compensating for the inhibitory PGE₂ effect, since these cytokines induce cells to produce higher H₂O₂ and TNF-α levels.

Keywords:

• Prostaglandin E₂
• cytokines
• monocytes
• P. brasiliensis
• hydrogen peroxide

Acknowledgements

This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) process n° 2005/55570 - 0.

Declaration of interest: The authors have no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This paper was first published online on Early Online on 30 April 2012.