Paracoccidioides brasiliensis induces secretion of IL-6 and IL-8 by lung epithelial cells. Modulation of host cytokine levels by fungal proteases

Abstract

Paracoccidioides brasiliensis is a pathogenic, dimorphic fungus that causes paracoccidioidomycosis, a systemic human mycosis that is highly prevalent in Latin America. In this study, we demonstrated that P. brasiliensis yeasts induced interleukin (IL)-8 and IL-6 secretion by human lung epithelial A549 cells. However, tumor necrosis factor-α and interferon-γ were undetectable in these cultures. Moreover, P. brasiliensis yeasts induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 in A549 cells, and IL-8 and IL-6 secretion promoted by this fungus was dependent on activation of p38 MAPK and ERK 1/2. In addition, IL-8 and IL-6 levels were significantly higher in culture supernatants of A549 cells that were incubated with formaldehyde-fixed P. brasiliensis compared to cultures of cells that were infected with live yeasts. Our results indicate that the observed cytokine level differences were due to protease expression, in live yeasts, that degraded these cytokines. Degradation of human recombinant IL-8 and IL-6 by live P. brasiliensis was inhibited by AEBSF and aprotinin, suggesting that these proteases belong to a family of serine proteases. This is the first report showing that P. brasiliensis may modulate host inflammation by expressing proteases that degrade proinflammatory cytokines.

Identification of human plasma proteins associated with the cell wall of the pathogenic fungusParacoccidioides brasiliensis

“…Recently, Maza et al . () showed that P. brasiliensis extracellular proteases degrade proinflammatory cytokines. Therefore, host protease inhibitors would be an obvious defense mechanism by neutralizing fungal proteases involved in infection.…”

“…Extracellular proteases can play important roles in pathogenic fungal nutrition, tissue invasion, and host immune system evasion (Naglik et al, 2003). Recently, Maza et al (2012) showed that P. brasiliensis extracellular proteases degrade proinflammatory cytokines. Therefore, host protease inhibitors would be an obvious defense mechanism by neutralizing fungal proteases involved in infection.…”

A novel renal epithelial cell in vitro assay to assessCandida albicansvirulence

“…13 Our results clearly demonstrate that renal epithelial cells are capable of initiating an immune response to fungal pathogens, similar to other epithelial cell types. 18,54,58,60,72 Interactions between renal epithelial cells and fungal cells, using a cell culture monolayer, showed that C. albicans formed hyphae and penetrated into M-1 epithelial cells at 3 h post-infection. C. albicans had previously been shown to adhere to the HEK293 human kidney cell line, but chemokine and cytokine responses were not investigated.…”

“…Epithelial cells, including renal cortical epithelial cells, are known to be capable of initiating an innate immune response through proinflammatory cytokine production, e.g., IL-8, IL-6, and IL-1. 22,[54][55][56][57][58][59][60][61] We, therefore, chose to evaluate murine renal epithelial cells as the basis for the development of a new assay to allow in vitro assessment of C. albicans virulence.…”

Picfeltarraenin IA inhibits lipopolysaccharide-induced inflammatory cytokine production by the nuclear factor-κB pathway in human pulmonary epithelial A549 cells

“…The level of IL-8 produced is observed to correlate with the severity of lung injury (9). Several studies have suggested that the overexpression of IL-8 is essential to the pathophysiological changes observed in chronic inflammatory lung disease (10,11). The level of IL-8 is reportedly a crucial prognostic factor for acute respiratory distress syndrome-associated mortality (12).…”