Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway epithelial responses by inhibition of DUOX1 and EGFR
| Autor: | David E. Heppner, Willem de Jong, Robert A. Bauer, Edmund O'Brien, Aida Habibovic, Andrew C. Little, Albert van der Vliet, Milena Hristova, Karamatullah Danyal |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Physiology Bronchi medicine.disease_cause Protein Carbonylation 03 medical and health sciences chemistry.chemical_compound Allergen Physiology (medical) Administration Inhalation medicine Animals Humans Cysteine Sulfhydryl Compounds Acrolein Asthma chemistry.chemical_classification Chemistry Pyroglyphidae NADPH Oxidases Epithelial Cells Hydrogen Peroxide Cell Biology Allergens Interleukin-33 medicine.disease Dual Oxidases Immunity Innate respiratory tract diseases Enzyme Activation ErbB Receptors Mice Inbred C57BL Interleukin 33 src-Family Kinases 030104 developmental biology Biochemistry Immunology Dual oxidase 1 Electrophile Thiol Respiratory epithelium Calcium Aritcles |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 311:L913-L923 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | Acrolein is a major thiol-reactive component of cigarette smoke (CS) that is thought to contribute to increased asthma incidence associated with smoking. Here, we explored the effects of acute acrolein exposure on innate airway responses to two common airborne allergens, house dust mite and Alternaria alternata, and observed that acrolein exposure of C57BL/6 mice (5 ppm, 4 h) dramatically inhibited innate airway responses to subsequent allergen challenge, demonstrated by attenuated release of the epithelial-derived cytokines IL-33, IL-25, and IL-1α. Acrolein and other anti-inflammatory thiol-reactive electrophiles, cinnamaldehyde, curcumin, and sulforaphane, similarly inhibited allergen-induced production of these cytokines from human or murine airway epithelial cells in vitro. Based on our previous observations indicating the importance of Ca2+-dependent signaling, activation of the NADPH oxidase DUOX1, and Src/EGFR-dependent signaling in allergen-induced epithelial secretion of these cytokines, we explored the impact of acrolein on these pathways. Acrolein and other thiol-reactive electrophiles were found to dramatically prevent allergen-induced activation of DUOX1 as well as EGFR, and acrolein was capable of inhibiting EGFR tyrosine kinase activity via modification of C797. Biotin-labeling strategies indicated increased cysteine modification and carbonylation of Src, EGFR, as well as DUOX1, in response to acrolein exposure in vitro and in vivo, suggesting that direct alkylation of these proteins on accessible cysteine residues may be responsible for their inhibition. Collectively, our findings indicate a novel anti-inflammatory mechanism of CS-derived acrolein and other thiol-reactive electrophiles, by directly inhibiting DUOX1- and EGFR-mediated airway epithelial responses to airborne allergens. |
| Databáze: | OpenAIRE |
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