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.

ACKNOWLEDGMENTS

We have no conflicting financial interests.

The work was supported by grants from Deutsche Forschungsgemeinschaft (BR999, ECCPS), Sander Foundation (2007.070.2), and Deutsche Krebshilfe (109599). M.J. was supported by a grant from the Fritz-Thyssen-Stiftung and from the Medical Faculty, Goethe University Frankfurt. J.M. was supported by the Deutscher Akademischer Austauschdienst (DAAD).

We thank Esther Imelmann for her support in designing NGAL promoter deletion constructs.