Proteases from<i>Aspergillus fumigatus</i>Induce Interleukin (IL)–6 and IL‐8 Production in Airway Epithelial Cell Lines by Transcriptional Mechanisms

Borger, Pieter; Koeter, Gh; Timmerman, J. A. B.; Vellenga, Edo; Tomee, J. F. C.; Kauffman, Hf

doi:10.1086/315027

Cited by 143 publications

(108 citation statements)

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“…In the present study, we demonstrated that Pen c 13 induced IL-8 release from HAECs and that this effect was almost completely blocked by protease inhibitors. Extracts of dust mite and fungi have been shown to directly induce airway inflammation, characterized by IL-8 and IL-6 expression in the airway epithelium (7)(8)(9)(10). Although the precise role of Pen c 13 in allergic disease is unclear, fungal proteases have been linked to allergic asthma, and many of the Ags frequently implicated in disease are proteases.…”

Section: Discussionmentioning

confidence: 99%

“…M any aeroallergens have been shown to possess proteolytic activity; this is the case for house dust mite (Dermatophagoides pteronyssinus), which contains the serine proteases, Der p 3 and Der p 9, and the cysteine protease, Der p 1 (1-3), cockroach extracts (4 -6), and house fungal extracts (Alternaria alternata, Cladosporium herbarum, and Aspergillus fumigatus) (7)(8)(9). Allergens with protease activities may be involved in the pathogenesis of asthma by proteolytic attack and direct activation of epithelial cells.…”

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confidence: 99%

“…Proteases from A. alternata, C. herbarum, and A. fumigatus induce the production of IL-8 and IL-6 by A549 cells and cause cell detachment (8,9). Furthermore, an extract of German cockroach (Blattella germanica) contains proteolytic activity that causes an increase in TNF-␣-induced IL-8 expression in human bronchial epithelial cells (4).…”

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confidence: 99%

“…Furthermore, an extract of German cockroach (Blattella germanica) contains proteolytic activity that causes an increase in TNF-␣-induced IL-8 expression in human bronchial epithelial cells (4). The effects of these aeroallergen proteases, acting via protease-activated receptors (PARs), 3 have been implicated in the regulation of the release of proinflammatory cytokines, such as eotaxin, GM-CSF, IL-6, and IL-8, by epithelial cells in a nonallergic inflammatory response (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). PARs appear to play a proinflammatory role by activating proinflammatory cytokines (11,12).…”

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confidence: 99%

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Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

Chiu

Perng

et al. 2007

The Journal of Immunology

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Allergenic serine proteases are important in the pathogenesis of asthma. One of these, Pen c 13, is the immunodominant allergen produced by Penicillium citrinum. Many serine proteases induce cytokine expression, but whether Pen c 13 does so in human respiratory epithelial cells is not known. In this study, we investigated whether Pen c 13 caused IL-8 release and activated protease-activated receptors (PARs) in airway epithelial cells. In airway-derived A549 cells and normal human airway epithelial cells, Pen c 13 induced IL-8 release in a dose-dependent manner. Pen c 13 also increased IL-8 release in a time-dependent manner in A549 cells. Pen c 13 cleaved PAR-1 and PAR-2 at their activation sites. Treatment with Pen c 13 induced intracellular Ca2+ mobilization and desensitized the cells to the action of other proteases and PAR-1 and PAR-2 agonists. Moreover, Pen c 13-mediated IL-8 release was significantly decreased in Ca2+-free medium and was abolished by the protease inhibitors, PMSF and 4-(2-aminoethyl) benzenesulfonyl fluoride. Blocking Abs against the cleavage sites of PAR-1 and PAR-2, but not of PAR-4, inhibited Pen c 13-induced IL-8 production, as did inhibition of phospholipase C. Pen c 13 induced IL-8 expression via activation of ERK 1/2, and not of p38 and JNK. In addition, treatment of A549 cells or normal human airway epithelial cells with Pen c 13 increased phosphorylation of ERK 1/2 by a Ca2+-dependent pathway. These finding show that Pen c 13 induces IL-8 release in airway epithelial cells and that this is dependent on PAR-1 and PAR-2 activation and intracellular calcium.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

Chiu

Perng

et al. 2007

The Journal of Immunology

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“…Secretion of cytokines from the airway epithelium contributes to the inflammation response. Cell stimulation assays show that increased cytokine secretion can be induced by both endogenous proteases from the coagulation cascade and inflammatory cells (Schoenmakers et al, 2005;Wang et al, 2006), as well as exogenous proteases derived from mites (King et al, 1998;Tomee et al, 1998), molds (Borger et al, 1999;Kauffmann et al, 2000), bacteria (Lourbakos et al, 2001;Ubl et al, 2002;Kida et al, 2007;, cockroaches (Bhat et al, 2003), and fish (Larsen et al, 2008). In addition to their well known role in digestion of dietary proteins, blood coagulation, and homeostasis, recent studies have revealed a novel role of serine proteases as signalling molecules acting via protease-activated receptors (PARs) in innate and adaptive immunity (Shpacovitch et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Purified sardine and king crab trypsin display individual differences in PAR-2-, NF-κB-, and IL-8 signaling

Larsen

Seternes

Bang

2011

Toxicological & Environmental Chemistry

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Respiratory symptoms are present in workers processing a great variety of seafood, including the salmon, sardine, and king crab industry. We have previously shown that salmon trypsin is able to generate DNA-binding of NF-κB and induce secretion of IL-8 from airway epithelial cells by activating PAR-2. In this study we explore if purified trypsins from king crab (Paralithodes camtschaticus) and sardine (Sardinops melanostictus) is able to induce similar effects in cell stimulation assays. Different types of seafood seem to display dissimilar irritant/allergic potencies in human airways and molecular modelling has identified divergent positions in the king crab trypsin compared to salmon trypsin that might influence upon the binding to the N-terminal end of PAR-2, which is a prerequisite for proteolytic activation of the receptor. This knowledge inspired us to investigate if we could detect differences in intracellular signalling pathways coupled to IL-8 in human airway epithelial cells (A549) following stimulation with purified king crab and sardine trypsin. Both sardine and king crab trypsin induce secretion of IL-8 from human airway epithelial cells in a concentration-dependent manner and generate DNA-binding of activated NF-κB. By the use of siRNA we can conclude that these effects are both mediated, at lest partly, through the activation of PAR-2. The king crab and sardine trypsin displays individual differences in transformation of the NF-κB signal, as high enzyme concentrations of king crab trypsin yields high levels of NF-κB that does not translate into increased secretion of IL-8 in the cell stimulation assays. The contribution of MEK/ERK, p38 and NF-κB to the secretion of IL-8 following stimulation with purified sardine and king crab trypsins were explored by the use of specificinhibitors. The results demonstrate that MEK/ERK and NF-κB are both required for purified sardine and king crab trypsin-induced secretion of IL-8 but via separate pathways. P38 was also found to contribute to the secretion of IL-8 by seemingly NF-kB-dependent processes.The data presented indicate that small structural variations in agonists may lead to differences in receptor activation and subsequent intracellular signalling.

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Induction of the specific allergic immune response is independent of proteases from the fungus Alternaria alternata

et al. 2013

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We have analyzed the importance of proteases for the induction of allergic responses against the mold Alternaria alternata. Responses induced in vivo with untreated or heat treated (protease inactivated) extracts were compared in BALB/c, C57BL/6, TLR4 KO, and MyD88 KO mice. In BALB/c mice, both extracts induced similar lung inflammation, upregulation of inflammatory mediators, Th2 cytokines, and Alternaria-specific antibodies. However heat inactivation abrogated polyclonal IgE production. Similar results were obtained in C57BL/6 albeit lung expression of some Th2 mediators was decreased in mice stimulated with the heat-treated extract. Treatment of the extract with protease inhibitors did not affect the induction of the allergic response either, except again for the polyclonal IgE response. Th2 responses and lung inflammation were readily induced in TLR4 knockout mice. In contrast, lung inflammation, Th2 responses, cytokine productions, and antibody synthesis were strongly suppressed in MyD88-deficient mice. Early lung IL-33 and IL-1-α expression were also suppressed. In conclusion, albeit some heat labile proteases are required for the stimulation of the polyclonal IgE secretion, fungal proteases, and TLR4 signaling are not required while MyD88 is essential for triggering the systemic immune response and for the development of lung allergic inflammation in response to Alternaria extracts. Keywords:Alternaria alternata r Animal models r Asthma r Eosinophils r proteases Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllergy is the clinical manifestation of a dysregulated immune response characterized by the production of IgE directed against foreign molecules. In this context, allergic asthma has become Correspondence: Dr. Olivier Denis e-mail: odenis@wiv-isp.be a major public healthcare problem. Asthma patients suffer from repeated attacks of breathlessness, cough, and wheeze occurring secondary to bronchoconstriction in the setting of airway hyper-responsiveness, mucus hypersecretion, and airway remodeling. Their airways are infiltrated by Th2 cells, which predominantly secrete IL-4, IL-5, and IL-13. These cytokines induce IgE production, cause eosinophilia, stimulate mast cells, promote leukocytosis, provoke airway hyper-reactivity, and may also participate in the characteristic airway remodeling of asthma [1,2].C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 908Olivier Denis et al. Eur. J. Immunol. 2013. 43: 907-917 In allergic asthma, these responses are initially triggered by aeroallergens entering into the lungs. Obviously the respiratory mucosa is continuously exposed to a wide variety of environmental, nonreplicating, nonpathogenic antigens. Usually these encounters induce a state of peripheral tolerance or hyporesponsiveness rather than active immunity. This T-cell tolerance induced by respiratory exposure is partially mediated by pulmonary DCs secreting .Respiratory allergens, however, have the striki...

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Proteases fromAspergillus fumigatusInduce Interleukin (IL)–6 and IL‐8 Production in Airway Epithelial Cell Lines by Transcriptional Mechanisms

Cited by 143 publications

References 33 publications

Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

Purified sardine and king crab trypsin display individual differences in PAR-2-, NF-κB-, and IL-8 signaling

Induction of the specific allergic immune response is independent of proteases from the fungus Alternaria alternata

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