Induction of Group IVC Phospholipase A2 in Allergic Asthma: Transcriptional Regulation by TNF-α in Bronchoepithelial Cells
Authors
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.
Nick, Harry S.
Document Type
Journal ArticlePublication Date
2012-02-15Keywords
Aspergillus fumigatusAsthma
Group IV Phospholipases A2
Tumor Necrosis Factor-alpha
Allergy and Immunology
Genetics and Genomics
Pediatrics
Respiratory Tract Diseases
Metadata
Show full item recordAbstract
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.Source
Biochem J. 2012 Feb 15;442(1):127-37. doi:10.1042/BJ20111269. Link to article on publisher's site
DOI
10.1042/BJ20111269Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43849PubMed ID
22082005Related Resources
Link to article in PubMedRights
© 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.
ae974a485f413a2113503eed53cd6c53
10.1042/BJ20111269