| First Author | Bickford JS | Year | 2012 |
| Journal | Biochem J | Volume | 442 |
| Issue | 1 | Pages | 127-37 |
| PubMed ID | 22082005 | Mgi Jnum | J:331026 |
| Mgi Id | MGI:6870649 | Doi | 10.1042/BJ20111269 |
| Citation | Bickford JS, et al. (2012) Induction of group IVC phospholipase A2 in allergic asthma: transcriptional regulation by TNFalpha in bronchoepithelial cells. Biochem J 442(1):127-37 |
| abstractText | 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 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 PLA2 (phospholipase A2) [also known as cPLA2gamma (cytosolic PLA2gamma) or PLA2G4C]. Our results infer that A. fumigatus extract can induce cPLA2gamma levels directly in eosinophils, whereas induction in lung epithelial cells is most likely to be a consequence of TNFalpha (tumour necrosis factor alpha) secretion by A. fumigatus-activated macrophages. The mechanism of TNFalpha-dependent induction of cPLA2gamma gene expression was elucidated through a combination of promoter deletions, ChIP (chromatin immunoprecipitation) and overexpression studies in human bronchoepithelial cells, leading to the identification of functionally relevant CRE (cAMP-response element), NF-kappaB (nuclear factor kappaB) and E-box promoter elements. ChIP analysis demonstrated that RNA polymerase II, ATF-2 (activating transcription factor 2)-c-Jun, p65-p65 and USF (upstream stimulating factor) 1-USF2 complexes are recruited to the cPLA2gamma enhancer/promoter in response to TNFalpha, with overexpression and dominant-negative studies implying a strong level of co-operation and interplay between these factors. Overall, our results link cytokine-mediated alterations in cPLA2gamma gene expression with allergic asthma and outline a complex regulatory mechanism. |
