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Published online before print July 11, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0207090

Received for publication February 5, 2007.
Revised June 11, 2007.
Accepted for publication June 11, 2007.

Article

Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis

Enrico Orciuolo *@, Marta Stanzani {dagger}, Martina Canestraro *, Sara Galimberti *, Giovanni Carulli *, Russell Lewis {ddagger}, Mario Petrini *, and Krishna V. Komanduri {sect}

*Hematology Section, Department of Oncology, Transplant and Advances in Medicine, University of Pisa, Italy; {dagger}Institute of Hematology and Clinical Oncology ‘L. e A. Seràgnoli’, University of Bologna, Italy; and {ddagger}Department of Infectious Diseases Infection Control and Employee Health and {sect}Transplant Immunology Section, Department of Stem Cell Transplantation and Cellular Therapy, M.D. Anderson Cancer Center, Houston, Texas, USA

@ To whom correspondence should be addressed. E-mail: orci{at}sssup.it.


  Abstract

Aspergillus fumigatus (AF) is a ubiquitous mold and the most common cause of invasive aspergillosis (IA) in immunocompromised patients. In stem cell transplant recipients, IA now occurs most frequently in the setting of therapy with corticosteroids, including methylprednisolone (MP). We showed previously that gliotoxin (GT), an AF-derived mycotoxin, induces apoptosis in monocytes and dendritic cells, resulting in the suppression of AF-specific T cell responses. We examined the ability of GT to induce apoptosis in polymorphonuclear leukocytes (PMN) and assessed GT effects on important neutrophil functions, including phagocytic function, degranulation, myeloperoxidase activity, and the production of reactive oxygen species (ROS). In contrast to its effects on monocytes, PMN remained resistant to GT-mediated apoptosis. Although many essential neutrophil functions were unaffected, GT inhibited phagocytosis and also induced a decrease in ROS generation by PMN. In contrast, MP therapy potentiated ROS production, suggesting a mechanism that may facilitate tissue injury in IA. Distinct from its effects on untreated PMN, GT augmented ROS production in MP-treated PMN. Our results suggest that although GT may suppress the adaptive immune response, GT may also serve to increase PMN-mediated inflammation, which is likely to play an important role in tissue destruction in the setting of IA.

Key Words: reactive oxygen species • polymorphonuclear leukocytes






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