Exposure to mycotoxins increases the allergic immune response in a murine asthma model.

RATIONALE: Epidemiological studies have shown that indoor molds are associated with increased prevalence and exacerbation of respiratory symptoms and asthma. Mycotoxins, secondary metabolites of molds, may contribute to these effects. OBJECTIVES: To investigate the adjuvant activity of mycotoxins on allergic airway inflammation. METHODS: Balb/c mice were exposed via the airways to gliotoxin and via the intestine to patulin, sensitized with ovalbumin (OVA), and then analyzed in acute and chronic murine asthma models. In addition, the effect of mycotoxin exposure on dendritic cell (DC) function was investigated using murine bone marrow-derived DCs. MEASUREMENTS AND MAIN RESULTS: Exposure of mice to both mycotoxins enhanced dose-dependently airway hyperreactivity, eosinophilic lung inflammation, and OVA-specific IgE serum levels compared with mice that received only the antigen. These findings correlated with increased Th2 cytokine levels and decreased IFN-gamma production. Long-term mycotoxin exposure exacerbated chronic airway inflammation and airway remodeling. In vitro or in vivo mycotoxin exposure inhibited IL-12 production in maturing DCs and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. Mycotoxin exposure enhanced OVA-induced lung lipid peroxidation and moderately increased isoprostane levels in naive mice. Treatment of mycotoxin-exposed DCs with the antioxidants N-acetylcysteine or glutathione ethyl ester restored IL-12 secretion and pretreatment of exposed mice with N-acetylcysteine prevented the mycotoxin-induced increase of airway inflammation and AHR. CONCLUSIONS: Our results demonstrate that gliotoxin and patulin increase the allergic immune response in mice by modulating the Th1/Th2 balance via direct effects on IL-12 secretion in DCs and by inducing oxidative stress.

Alterations of A549 lung cell gene expression in response to biochemical toxins.

Health risks associated with the inhalation of potentially toxic materials have been a topic of great public concern. In vitro cellular analyses can provide mechanistic information on the molecular-level responses of lung-derived cell lines to a variety of these hazards. This understanding may be used to develop methods to reduce the damage from such toxins or to detect early stages of their effects. Here we describe an evaluation of the alterations in gene expression of an immortalized lung cell line (A549, human type II epithelia) to a variety of inhalation health hazards including etoposide, gliotoxin, streptolysin O, methyl methansesulfonate (MMS), and Triton X-100. The A549 cells display a dose-response relationship to each toxin with initial responses including alterations in metabolic activity, increases in membrane permeability, and initiation of response genes. In general, membrane-damaging agents (streptolysin O and Triton X-100) induce production of new ion channel proteins, structural proteins, and metabolic enzymes. Gliotoxin impacted the metabolic machinery, but also altered ion channels. Etoposide and MMS caused alterations in the cell cycle, induced DNA repair enzymes, and initiated apoptotic pathways, but MMS also induced immune response cascades. The mechanism of cell response to each toxin is supported by physiological analyses that indicated a fairly slow initiation of cell response to all compounds tested, except for Triton, which caused rapid decline in cell function due to solubilization of the cell membrane. However, Triton does induce production of a number of cell membrane-associated proteins and so its effects at low concentrations are likely translated throughout the cell. Together these results indicate a broader array of cellular responses to each of the test toxins than have previously been reported.

Gliotoxin and related epipolythiodioxopiperazines.

1. Gliotoxin belongs to the epipolythiodioxopiperazine class of secondary metabolites. These compounds show a diverse range of biological activity including antimicrobial, antifungal and antiviral properties. They also display potent in vitro and in vivo immunomodulating activity. 2. Their properties resulted in a number of early studies designed to exploit their possible chemotherapeutic value, although the general toxicity of most members of this class has precluded clinical use. 3. Most recently, their selective immunosuppressive properties have led to the possibility of ex vivo treatment of tissue to selectively remove immune cells responsible for tissue rejection. The mode of action of gliotoxin appears to be via covalent interaction to proteins through mixed disulphide formation and gliotoxin has been shown to inhibit a number of thiol requiring enzymes. 4. Gliotoxin is also a potent inducer of apoptotic cell death in a number of cells. Gliotoxin and other members of this class of toxins may be produced in vivo during the course of fungal infections and contribute to the aetiology of the disease.