Interleukin-15 increases Paracoccidioides brasiliensis killing by human neutrophils

Abstract

ABSTRACT:Interleukin-15 is a pro-inflammatory cytokine produced by a wide range of different cell types, especially monocytes and macrophages, in response to infective agents, playing a crucial and modulatory role in innate and adaptive immune response. Infections by intracellular microorganisms such as some bacteria, protozoa and fungi point out the role of IL-15 in the activation of monocytes/macrophages and neutrophils, a process that represents an important defense mechanism in early periods of infection during the development of innate immune response. The aims of the present study were to evaluate the effects of IL-15 on human neutrophil fungicidal activity against a high virulent Paracoccidioides brasiliensis strain (Pb18) and to verify whether this activity was mediated by oxidative metabolism such as the production of superoxide anion and H 2 O 2 and if it was associated with an alteration of cytokine (IL-8 and TNF-α) levels. Neutrophils from peripheral blood of healthy individuals were incubated in the presence and absence of IL-15 (12.5-250ng/ml) for 18h, at 37ºC, under tension of 5% CO 2 , then infected with Pb18 for 4h and evaluated for fungicidal activity, production of superoxide anion and H 2 O 2 , and quantification of cytokines IL-8 and TNF-α in the supernatant. Preincubation of neutrophils with IL-15 induced a significant increase in the fungicidal activity of such cells in a dose-dependent manner. After activation, there was an increase in the production of superoxide anion and H 2 O 2 by these cells, suggesting participation of such metabolites in fungicidal activity. Catalase inhibits fungicidal activity, confirming the role of H 2 O 2 in fungus killing. However, the levels of TNF-α and IL-8 were not modified after incubation with IL-15, which suggests that its role is not mediated by those cytokines. Taken together, results showed that IL-15 had a modulatory effect on human neutrophils infected in vitro with a high virulent strain of P. brasiliensis, which was characterized by an increased fungicidal activity mediated by a dependent mechanism of oxidative metabolism.

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.…”

Human neutrophils produce extracellular traps against Paracoccidioides brasiliensis

“…Other studies have shown that cytokines such as IL-15, IL-8, IFN-c, granulocyte macrophage colony-stimulating factor (GM-CSF) and TNF-a increase the fungicidal/fungistatic effect of these cells (Kurita et al, 1999a(Kurita et al, , 2000Rodrigues et al, 2007;Tavian et al, 2008). Interestingly, the antifungal activity of IFN-c, TNF-a and GM-CSF is exerted in a dosedependent manner and this response is correlated with production of reactive oxygen species (ROS) (Rodrigues et al, 2007).…”

Phenotypic and Functional Characterization of NK Cells in Human Immune Response against the Dimorphic Fungus Paracoccidioides brasiliensis

“…In Candida albicans infection, IL-15 acts as a potent stimulus to the proinflammatory and antifungicidal activity of human neutrophils and monocytes (38). Neutrophils treated with IL-15 also show improved activity against P. brasiliensis yeast cells associated with the elevated production of reactive oxygen intermediaries (15).…”

“…Determination of the cytotoxic activity of NK cells against P. brasiliensis yeast cells and against target cells A CFU assay was performed as previously described (15), with minor modifications. In short, P. brasiliensis yeast cells were incubated either with or without 2 3 10 5 NK cells (ratio 1:250).…”