Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: implications for immunosuppressive activities.
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 FcepsilonRI-dependent or -independent mast cell activation, including degranulation, leukotriene C4 secretion, and TNF-alpha and IL-13 production. Gliotoxin also suppressed intracellular Ca2+ rise through store-operated Ca2+ channels with a minimal effect on depletion of internal Ca2+ 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.
Niide
Osamu
O
Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchikami-cho Itabashi-ku, Tokyo 173-8610, Japan.
Suzuki
Yoshihiro
Y
Yoshimaru
Tetsuro
T
Inoue
Toshio
T
Takayama
Tadatoshi
T
Ra
Chisei
C
D000818:Animals; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000276:immunology*; D015550:Cell Degranulation; D002478:Cells, Cultured; D005912:Gliotoxin / Q000494:pharmacology*; D006636:Histamine Release; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018793:Interleukin-13 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D017455:Receptors, IgE / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007166:Immunosuppressive Agents; D018793:Interleukin-13; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D017997:Leukotriene C4; D005912:Gliotoxin; D002118:Calcium