The chemistry and biology of the immunomodulating agent gliotoxin and related epipolythiodioxopiperazines

Cell Lysis Induced by Ricin D and Ricin E in Various Cell Lines

“…5 8) It is generally considered that apoptosis is an active process and may involve the de novo synthesis or activation of an endogenous Ca 2 + /Mg2 + -dependent endonuclease. 21,28) Thus, protein synthesis inhibitors such as cycloheximide and actinomycin-D can inhibit glucocorticoid-induced apoptosis in rat thymocytes,24) and radiationinduced apoptosis in lymphocytes. 23) However, this may not be the case for ricin and diphtheria toxin, s lnce they themselves are potent inhibitors of protein ~:ynthesis.…”

Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition

“…Gliotoxin possesses immunomodulating activity: it stimulates lymphocyte proliferation, and induces T cell cytotoxicity and lymphokine release by T cells (6)(7)(8)(9). Gliotoxin (10-100 nM) was found to inhibit phagocytic activity of peritoneal and circulating macrophages (6,7,9) at concentrations lower than those required to cause apoptosis of HSCs.…”

“…Gliotoxin (10-100 nM) was found to inhibit phagocytic activity of peritoneal and circulating macrophages (6,7,9) at concentrations lower than those required to cause apoptosis of HSCs. High concentration of gliotoxin (>1 μM) induces reactive oxygen species (ROS)-mediated apoptosis of peritoneal macrophages, independent of the inhibition of phagocytosis (8). The role of hepatic macrophages Kupffer cells extends from defense against invading microbes and clearance of toxic substances to liver growth and immune regulation (10)(11)(12)(13).…”

Frequency and Species Distribution of Gliotoxin-Producing Aspergillus Isolates Recovered from Patients at a Tertiary-Care Cancer Center

“…One of the most abundantly produced metabolites is the epipolythiodioxopiperazine metabolite gliotoxin, which exhibits a diverse array of biologic effects on the immune system. Gliotoxin inhibits macrophage and polymorphonuclear cell function and the generation of alloreactive cytotoxic T cells (2,3,7,13,14) and suppresses activation of the nuclear transcription factor NFB-the central regulator of gene transcription for inflammatory cytokines, growth factor receptors, and cell adhesion molecules (9). In immunocompetent mice, the administration of gliotoxin results in a level of immunosuppression sufficient to render animals susceptible to fatal invasive aspergillosis after challenge with A. fumigatus conidia (11).…”