Gliotoxin, a metabolite of Aspergillus fumigatus, inhibits phagocytosis of macrophages at concentrations of 20-50 ng/ml. Pretreatment of stimulator cells in mixed lymphocyte cultures with gliotoxin (1QQ ng/ml) abrogates induction of alloreactive cytotoxic T cells. The presence of gliotoxin 48 hr after initiation of cytotoxic T-cell induction has no effect. Inhibition of cytotoxic T-cell induction by gliotoxin at low concentrations, acting on the stimulator cells, can be overridden by concanavajin A-activated cell supernatants. Gliotoxin does not induce immediate cell-surfpce antigen modification on target cells. The possible role of gliotoxin in the etiology of A. fumigatus-related diseases is discussed.Fungal metabolites have been extensively investigated for their antimicrobial activities since the fortuitous discovery of penicillin by Fleming. Little is known, however, apart from general toxicological studies on eukaryotic cells, about their effect on specific tissue such as the hemopoietic system. One fungal metabolite, cyclosporin A, has recently gained worldwide attention as a potent immunosuppressive agent. Cyclosporin A has been investigated as an immunoregulatory agent in clinical practice, such as organ transplantation, as well as a tool in fundamental immunological research (1). It appears to act on the T lymphocyte, especially the T helper subset responsible for release of interleukin 2 after antigen recognition (1). Problems associated with cyclosporin A are nephrotoxicity, relatively high concentrations required for activity, and its low solubility in aqueous solutions.Aspergillus fumigatus, a member of the order Eurotiales, has been shown to be associated with a number of lung diseases in vertebrates including man (2-4). A. fumigatus produces a variety of toxic substances including gliotoxin, a compound containing an epidithiadioxopiperazine ring, which possesses antimicrobial activity in vitro (5). However, little is known regarding the effect of any of these fungal metabolites in vivo and their possible role in the etiology of A. fumigatus-related diseases.We now report on the immunosuppressive and anti-phagocytic activity of gliotoxin in vitro and its possible role in the pathogenesis of A. fumigatus-induced diseases.
When cultured in titro, Aspergillus fumigatus generated a metabolite(s) with anti-phagocytic activity as tested by macrophage adherence to plastic and phagocytosis of particulate matter. The metabolite(s) appeared after 3 d culture and reached a peak concentration after 5-6 d. The action of the anti-phagocytic agent(s) was rapid (5-15 min) and appeared not to alter membrane permeability or cause rapid cell death. Treatment of stimulator spleen cells with the agent(s) inhibited their ability to induce alloreactive and major histocompatibility complex restricted cytotoxic T cells. The metabolite(s) was chloroform-soluble and separated into three biologically active compounds on thin-layer chromatography. These compounds were purified > 1000-fold and one of them was identified as gliotoxin, a known metabolite of A. fumigatus, based upon NMR and IR spectroscopy, mass spectrometry, biological properties and other data.
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