Interleukin-10-induced neutrophil gelatinase-associated lipocalin production in macrophages with consequences for tumor growth

Mol Cell Biol. 2012 Oct;32(19):3938-48. doi: 10.1128/MCB.00413-12. Epub 2012 Jul 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / immunology*
  • Breast / cytology
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Humans
  • Interleukin-10 / immunology*
  • Janus Kinases / immunology
  • Lipocalin-2
  • Lipocalins / genetics
  • Lipocalins / immunology*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology*
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / metabolism


  • Acute-Phase Proteins
  • CCAAT-Enhancer-Binding Protein-beta
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Interleukin-10
  • Janus Kinases