title: Interleukin-10-induced neutrophil gelatinase-associated lipocalin production in macrophages with consequences for tumor growth.
abstract: Tumor cell-derived factors, such as interleukin 10 (IL-10), polarize macrophages toward a regulatory M2 phenotype, characterized by the expression of anti-inflammatory cytokines and protumorigenic mediators. Here we explored molecular mechanisms allowing IL-10 to upregulate the protumorigenic protein NGAL in primary human macrophages. Reporter assays of full-length or deletion constructs of the NGAL promoter provided evidence that NGAL production is STAT3 dependent, activated downstream of the IL-10-Janus kinase (Jak) axis, as well as being C/EBPβ dependent. The involvement of STAT3 and C/EBPβ was shown by chromatin immunoprecipitation (ChIP) and ChIP-Western analysis, as well as decoy oligonucleotides scavenging both STAT3 and C/EBPβ in human macrophages. Furthermore, the production of NGAL in macrophages in response to IL-10 induces cellular growth and proliferation of MCF-7 breast cancer cells. We conclude that both STAT3 and C/EBPβ are needed to elicit IL-10-mediated NGAL expression in primary human macrophages. Macrophage-secreted NGAL shapes the protumorigenic macrophage phenotype to promote growth of MCF-7 breast cancer cells. Our data point to a macrophage-dependent IL-10-STAT3-NGAL axis that might contribute to tumor progression.
authors.affiliation: Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Jung
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.forename: Michaela
authors.initials: M
authors.lastname: Tausendschön
authors.forename: Javier
authors.initials: J
authors.lastname: Mora
authors.forename: Bilge
authors.initials: B
authors.lastname: Ören
authors.forename: Anna
authors.initials: A
authors.lastname: Sola
authors.forename: Georgina
authors.initials: G
authors.lastname: Hotter
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Muta
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology*; D001940:Breast / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D053612:Janus Kinases / Q000276:immunology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D053612:Janus Kinases