Proteases fromAspergillus fumigatusInduce Release of Proinflammatory Cytokines and Cell Detachment in Airway Epithelial Cell Lines

Abstract

Aspergillus fumigatus is a pathogen causing diverse respiratory disorders. Several studies have suggested that fungal proteases may play a role in the pathogenicity of fungi. Since the airways are the most common route for entry of A. fumigatus, this study focused on the ability of fungal proteases to induce the release of proinflammatory cytokines and to cause cell detachment in human pulmonary epithelial cell lines. It was shown that fungal serine protease activity induced the production of interleukin (IL)-8 and IL-6 and monocyte chemotactic protein-1 and caused cell detachment in a dose-dependent fashion. Chymostatin, antipain, phenylmethylsulfonyl fluoride, and heat treatment completely inhibited fungal protease activity, cytokine production and cell detachment; antileukoprotease partially inhibited these activities. By causing cell detachment, fungal proteases may decrease the physical barrier function of the epithelium; however, by eliciting a cytokine response, the epithelium may signal the mucosal inflammatory response against A. fumigatus.

Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis

“…A. fumigatus proteases can induce IL-8 gene expression by transcription mechanisms involving enhanced DNA binding of NF-kB [29,30]. Since NF-kB is inhibited by inhibitory factor (IF)-kB, NF-kB activation may also be a target for therapy to control inflammation in ABPA.…”

Identification and expression of an allergen Asp f 13 from Aspergillus fumigatus and epitope mapping using human IgE antibodies and rabbit polyclonal antibodies

“…Dust mite serine protease allergens have been shown to have a direct effect on epithelial integrity and permeability [36], to cause mast cell degranulation in a non-IgEdependent manner [37], and to induce cytokine release from the respiratory epithelium [38]. Culture filtrates from A. fumigatus cause cell detachment of pulmonary epithelial cell lines and induce the production of proinflammatory cytokines [39]. Allergen-associated proteases may contribute to allergenicity by causing detachment of the epithelium, resulting in chronic damage to the epithelial surface layers, thus allowing penetration of antigens into the tissue and stimulating the release of proinflammatory cytokines from respiratory epithelium cells.…”

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

“…A fumigatus), but not large conidia Aspergillus spp, seem to be associated with impaired allograft survival in this population (138). Although the biological mechanism responsible for Aspergillus-induced BOS has not been clearly established, a similar chronic inflammatory process due to upregulated proinflammatory cytokines causing cell detachment in human pulmonary epithelial cell lines has been suggested (28).…”

“…Bacterial invasion in the urinary tract of kidney transplant recipients or in the respiratory tract of lung transplant recipients may also cause an inflammatory response and cytokine activation contributing to allograft dysfunction (26,27). A chronic inflammatory process due to upregulated proinflammatory cytokines causing cell detachment in human pulmonary epithelial cell lines has been suggested as a possible mechanism of damage in the development of BOS by Aspergillus (28). Other mechanisms contributing to impaired allograft function and survival include sepsisassociated ischemia due to hemodynamic instability (29), acute rejection due to minimization of immunosuppression for clearance of viral infections (30) and direct drug toxicity (e.g.…”