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

Link to article in PubMed

PubMed ID

22082005

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