Herbsttagung Programm & Abstracts - Deutsche Gesellschaft für ...

Role of TNFAIP2 in Legionella pneumophila-induced pulmonary inflammation
Du Bois I 1,2 , Marsico A 3 , Becher A 4 , Bertrams W 1,2 , Sittka A 1,2 , Schulz C 1,2 , Vingron M 3 , Suttorp N 4 ,
Hippenstiel S 4 , Schmeck B 1,2
1 FORSYS Partner Research Group “Systems Biology of Lung Inflammation”; 2 Molecular
Pulmonology/iLung, UGMLC, German Center for Lung Research, Philipps University Marburg; 3 Max
Planck Institute for Molecular Genetics, Berlin; 4 Medizinische Klinik m.S. Infektiologie und
Pneumologie, Charité – Universitätsmedizin Berlin
Abstract:
Legionella pneumophila (L. pneumophila) is an important causative agent of severe pneumonia in
humans. The human alveolar epithelium and macrophages constitute the main cellular targets for
inhaled microorganisms and play a key role in the initiation of the innate immune response and the
defence against respiratory infection. Recent studies have highlighted an important role for chromatin
modifications in controlling the expression of inflammatory genes. Hence, human alveolar epithelial
cells (A549) were infected with L. pneumophila, and polymerase II recruitment and acetylation of
histone H4 were analyzed in a genome-wide manner by ChIP-Seq (chromatin immunoprecipitation
followed by massive parallel DNA sequencing). Preliminary analysis of these data revealed a strong
recruitment of polymerase II to the TNFAIP2 gene locus. TNFAIP2 (also called primary response gene
B94 protein) was originally described as a novel tumor necrosis factor-α (TNF-α)-induced gene in
human endothelial cells. Since the function of TNFAIP2 is still unclear, the aim of this study was to
characterize the role of TNFAIP2 in human lung inflammation. TNFAIP2 mRNA and protein
expression is induced by L. pneumophila in A549 cells and blood derived macrophages. In contrast,
its expression cannot be induced by human (Pan/99 (H3N2)), nor by avian (Dk/Alb (H12N5)) influenza
virus in A549 cells. Studies with specific MAP-kinase and NF-κB inhibitors show that L. pneumophilainduced
TNFAIP2 expression is dependent on NF-κB, and binding of the NF-κB subunit p50 and p65
to the TNFAIP2 gene promoter could be confirmed by ChIP analysis. Knockdown of TNFAIP2 leads to
reduced intracellular replication of L. pneumophila in A549 cells. Immunohistochemical staining of
human lung shows increased expression of TNFAIP2 almost exclusively in alveolar macrophages. We
conclude that TNFAIP2 may have a fundamental role in the immune response to L. pneumophila.
However, the precise mode of action has to be further characterized.
12