PMID:22294049

Citation	Song, KS, Yoon, JH, Kim, KS and Ahn, DW (2012) c-Ets1 inhibits the interaction of NF-κB and CREB, and downregulates IL-1β-induced MUC5AC overproduction during airway inflammation. Mucosal Immunol 5:207-15
Abstract	Mucin hypersecretion is frequently observed in many inflammatory diseases of the human respiratory tract. As mucin hypersecretion refers to uncontrolled mucin expression and secretion during inflammation, studies examining the negative control mechanisms of mucin hypersecretion are vital in developing novel therapeutic medications. We hypothesized that the c-Ets1 induced by interleukin (IL)-1β would decrease MUC5AC overproduction by inhibiting the interaction of NF-κB with cAMP response element-binding protein (CREB) in vivo. Stimulation with IL-1β caused the direct binding of NF-κB and CREB to the MUC5AC promoter, thus increasing MUC5AC gene expression. However, IL-1β-induced MUC5AC messenger RNA levels were surprizingly downregulated by c-Ets1 (located -938 to -930). Interestingly, c-Ets1 also suppressed IL-1β-induced MUC5AC gene expression in vitro and in vivo by disrupting the interaction of NF-κB with CREB on the MUC5AC promoter. In addition, c-Ets1 also inhibited significant morphologic changes and inflammatory cell infiltration after IL-1β exposure in mouse lungs infected with either wild-type or shRNA-c-Ets1. Moreover, reactive oxygen species produced by NOX4 increased c-Ets1 gene expression and MUC5AC gene expression in alveolar macrophages from bronchoalveolar lavage fluid. These results suggest a molecular paradigm for the establishment of a novel mechanism underlying the negative regulation of mucin overproduction, thus enhancing our understanding of airway inflammation.
Links	PubMed PMC3282431 Online version:10.1038/mi.2011.67
Keywords	Animals; Cell Line; Cyclic AMP Response Element-Binding Protein/genetics; Cyclic AMP Response Element-Binding Protein/immunology; Cyclic AMP Response Element-Binding Protein/metabolism; Gene Expression Regulation/genetics; Humans; Inflammation Mediators/metabolism; Interleukin-1beta/immunology; Interleukin-1beta/metabolism; Metaplasia/genetics; Metaplasia/immunology; Mice; Mice, Inbred C57BL; Mucin 5AC/genetics; Mucin 5AC/immunology; Mucin 5AC/metabolism; Mucus/secretion; NF-kappa B/genetics; NF-kappa B/immunology; NF-kappa B/metabolism; Pneumonia/genetics; Pneumonia/immunology; Pneumonia/metabolism; Pneumonia/pathology; Promoter Regions, Genetic/genetics; Protein Binding/genetics; Proto-Oncogene Protein c-ets-1/genetics; Proto-Oncogene Protein c-ets-1/immunology; Proto-Oncogene Protein c-ets-1/metabolism; RNA, Small Interfering/genetics; Reactive Oxygen Species/metabolism; Respiratory Mucosa/immunology; Respiratory Mucosa/metabolism; Respiratory Mucosa/pathology; Transgenes/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:ETS1		GO:0050728: negative regulation of inflammatory response	ECO:0000315:		P		Figure 4 shows that mutants of the ETS1 gene have increased protein levels of the proteins secreted during inflammatory response.	complete CACAO 4887
MOUSE:ETS1	involved_in	GO:0050728: negative regulation of inflammatory response	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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