Pneumologie 2013; 67 - P259
DOI: 10.1055/s-0033-1334622

Role of TNFAIP2 in Legionella pneumophila-induced pulmonary inflammation

I Du Bois 1, A Marsico 2, A Becher 3, W Bertrams 1, A Sittka 1, C Schulz 1, M Vingron 2, N Suttorp 3, S Hippenstiel 3, B Schmeck 1
  • 1Philipps Universität Marburg
  • 2Max Planck Institute for Molecular Genetics, Berlin
  • 3Charité-Universitätsmedizin Berlin, Med. Klinik m.S. Infektiologie und Pneumologie

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. pneumophila-induced 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 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.