Paracoccidioides brasiliensiskilling by IFN-γ, TNF-α and GM-CSF activated human neutrophils: role for oxygen metabolites

Abstract

Paracoccidioidomycosis, a deep mycosis endemic in Latin America, is a chronic granulomatous disease caused by the fungus Paracoccidioides brasiliensis. Phagocytic cells play a critical role against the fungus and several papers show the effects of activator and suppressive cytokines on macrophage and monocyte functions. However, the studies focusing on polymorphonuclear neutrophils (PMNs) antifungal functions are scarcer. Thus, the objective of the present paper was to assess the capacity of human PMNs to kill virulent P. brasiliensis strain in vitro, before and after priming with different cytokines. Moreover, the involvement of oxygen metabolites in this activity was evaluated. Nonactivated cells failed to exhibit antifungal activity. However, when these cells were IFN-gamma, TNF-alpha or GM-CSF activated, a significative fungicidal activity was detected. This process was significantly inhibited when P. brasiliensis challenge occurred in presence of catalase (CAT - a scavenger of H2O2) and superoxide dismutase (SOD - a scavenger of superoxide anion). From these results it is concluded that cytokines activation is required for P. brasiliensis killing by human PMNs, and that H2O2 and superoxide anion participate as effectors molecules in this process.

Role of TLR2 and TLR4 in Human Neutrophil Functions AgainstParacoccidioides brasiliensis

“…We confirmed our previous studies showing that GM-CSF, IL-15, TNF-a and IFN-c activate human neutrophils inducing these cells to release higher H 2 O 2 levels and fungicidal activity against Pb [17,18,37]. However, both H 2 O 2 release and fungicidal Figure 3 Role of TLR2 and TLR4 on H 2 O 2 production.…”

“…Nonetheless, some studies show that neutrophil functions, including fungus killing, require activation with cytokines and other factors. In our laboratory, IFN-c, TNF-a, granulocytemacrophage colony-stimulating factor (GM-CSF) and IL-15 have been observed to activate human neutrophils for fungicidal activity by a mechanism dependent on H 2 O 2 and superoxide anion [17,18].…”

The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk

“…Although being dispensable for the recruitment of neutrophils in our as well as other model systems (65), IFN-␥ is known to induce neutrophil phagocytosis (66), microbicidal activity (67), and survival (68). We propose that CD4 ϩ T cell-derived IFN-␥ must act locally on neutrophils to activate their anti-Helicobacter properties.…”

Imunologia da paracoccidioidomicose

“…33 Human polymorphonuclear cells (PMN) are present in large amounts in infected tissues and they play an important role in fungicidal activity against P. brasiliensis through mechanisms dependent on oxygen metabolites such as H 2 O 2 and superoxide anion, when these cells are stimulated with IFN-γ, TNF-α, GM-CSF and IL-15. 34,35 PMN are essential in the early stages of infection, conferring resistance to the host and contributing to the development of an effective immune response against P. brasiliensis. PMN also produce large amounts of prostaglandin E2 and leukotrienes, perpetuating edema and inflammation but minimizing cell damage caused by monocytes.…”