UMMS Affiliation
Department of Pediatrics; Gene Therapy Center
Publication Date
2012-02-15
Document Type
Article
Subjects
Aspergillus fumigatus; Asthma; Group IV Phospholipases A2; Tumor Necrosis Factor-alpha
Disciplines
Allergy and Immunology | Genetics and Genomics | Pediatrics | Respiratory Tract Diseases
Abstract
Airway inflammation in allergen-induced asthma is associated with eicosanoid release. These bioactive lipids exhibit anti- and pro-inflammatory activities with relevance to pulmonary pathophysiology. We hypothesized that sensitization/challenge using an extract from the ubiquitous fungus, Aspergillus fumigatus (Af), in a mouse model of allergic asthma would result in altered phospholipase gene expression, thus modulating the downstream eicosanoid pathway. We observed the most significant induction in the group IVC phospholipase A2 (cPLA2γ or PLA2G4C). Our results infer that Af extract can induce cPLA2γ levels directly in eosinophils while induction in lung epithelial cells is most likely a consequence of TNF-α secretion by Af-activated macrophages. The mechanism of TNF-α-dependent induction of cPLA2γ gene expression was elucidated through a combination of promoter deletions, ChIP and overexpression studies in human bronchoepithelial cells, leading to the identification of functionally relevant CRE, NF-κB and E-box promoter elements. ChIP analysis demonstrated that RNA polymerase II, c-Jun/ATF-2, p65/p65 and USF1/USF2 complexes are recruited to the cPLA2γ enhancer/promoter in response to TNF-α with overexpression and dominant negative studies implying a strong level of cooperation and interplay between these factors. Overall, our data link cytokine-mediated alterations in cPLA2γ gene expression with allergic asthma and outline a complex regulatory mechanism.
Rights and Permissions
© The Authors Journal compilation © 2012 Biochemical Society
Authors' accepted manuscript posted as allowed by the publisher's author rights policy at http://www.biochemj.org/bj/bji2a.htm. The Version of Record (VoR) is available at www.biochemj.org.
DOI of Published Version
10.1042/BJ20111269
Source
Biochem J. 2012 Feb 15;442(1):127-37. doi:10.1042/BJ20111269. Link to article on publisher's site
Journal/Book/Conference Title
The Biochemical journal
Related Resources
PubMed ID
22082005
Repository Citation
Bickford, Justin S.; Newsom, Kimberly J.; Herlihy, John-David; Mueller, Christian; Keeler, Benjamin; Qiu, Xiaolei; Walters, Jewell N.; Su, Nan; Wallet, Shannon M.; Flotte, Terence R.; and Nick, Harry S., "Induction of Group IVC Phospholipase A2 in Allergic Asthma: Transcriptional Regulation by TNF-α in Bronchoepithelial Cells" (2012). Pulmonary and Allergy. 61.
https://escholarship.umassmed.edu/peds_pulmonary/61
Included in
Allergy and Immunology Commons, Genetics and Genomics Commons, Pediatrics Commons, Respiratory Tract Diseases Commons