Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: Implications for immunosuppressive activities

• Published in: Clinical Immunology 2006, Vol.118 (1), p.108-116
• Main Authors: Niide, Osamu, Suzuki, Yoshihiro, Yoshimaru, Tetsuro, Inoue, Toshio, Takayama, Tadatoshi, Ra, Chisei
• Format: Article
• Language: English
• Subjects: Animals; Aspergillus; Biological and medical sciences; Calcium - physiology; Calcium Signaling - immunology; Candida; Cell Degranulation; Cells, Cultured; FcεRI; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Fungal metabolite; Gliotoxin; Gliotoxin - pharmacology; Histamine Release; IgE; Immunopathology; Immunosuppression; Immunosuppressive Agents - pharmacology; Interleukin-13 - metabolism; Leukotriene C4 - metabolism; Mast cell; Mast Cells - drug effects; Mast Cells - immunology; Mast Cells - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Structure; Receptors, IgE - antagonists & inhibitors; Store-operated calcium entry; Superoxide; Superoxides - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1521-6616; 1521-7035; 1365-2567
• DOI: 10.1016/j.clim.2005.08.012

Fungal secondary metabolites such as gliotoxin, an epipolythiodioxopiperazine toxin produced by pathogenic fungi like Candida and Aspergillus, possess immunosuppressive activities and have been thought to contribute to pathology of fungal infections in animals and humans. Since recent studies show that mast cell plays a crucial role in the front of host defense, we examined whether fungal secondary metabolites affected mast cell activation. We found that gliotoxin had suppressive effects on FcεRI-dependent or -independent mast cell activation, including degranulation, leukotriene C 4 secretion, and TNF-α and IL-13 production. Gliotoxin also suppressed intracellular Ca 2+ rise through store-operated Ca 2+ channels with a minimal effect on depletion of internal Ca 2+ stores. Finally, gliotoxin induced intracellular production of superoxide possibly through a thiol redox cycling, which appeared to mediate suppressive effects on mast cell activation. These findings suggest that suppression of mast cell activation might contribute to the establishment of infections with gliotoxin-producing fungi.