IL-10 suppresses TNF-α-induced expression of human aromatase gene in mammary adipose tissue

Gabriela Martínez-Chacón, Kristy A. Brown, Maria M Docanto, Himanshu Kumar, Seppo Salminen, Niina Saarinen, Sari Mäkelä

Research output: Contribution to journalArticleScientificpeer-review

9 Citations (Scopus)

Abstract

White adipose tissue inflammation is linked with increased aromatase gene expression and estrogen production, a major risk factor for breast cancer in obese postmenopausal women. TNF-α, a proinflammatory cytokine, is a key driver of aromatase promoter I.4-mediated expression in adipose tissue. In this study, we have shown that IL-10, an anti-inflammatory cytokine, suppressed both TNF-α-stimulated human aromatase reporter-luciferase (hARO-Luc) expression in mouse bone marrow mesenchymal stromal cells and aromatase gene expression in human breast adipose stromal cells (ASCs). IL-10 blocked TNF-α-stimulated ERK1/2 activation in ASCs, suggesting an inhibitory effect through the MAPK signaling pathway. The links among obesity, IL-10, and aromatase were confirmed in ovariectomized (OVX) hARO-Luc mice, where increased adiposity was associated with upregulation of aromatase reporter activity and reduced IL-10 level in the mammary fat pad. OVX mice also exhibited changes in gut microbiota, similar to that in obese women, indicating altered immune function. In summary, our results suggest that increased adiposity, induced by the lack of ovarian hormones, results in enhanced expression of aromatase in mammary adipose tissue, mediated by reduction in local IL-10. These findings may bring new insights into the mechanisms involved in the development of postmenopausal breast cancer, as well as novel approaches for prevention.-Martínez-Chacón, G., Brown, K. A., Docanto, M. M., Kumar, H., Salminen, S., Saarinen, N., Mäkelä, S. IL-10 suppresses TNF-α-induced expression of human aromatase gene in mammary adipose tissue.

Original languageEnglish
Pages (from-to)3361-3370
Number of pages10
JournalFASEB Journal
Volume32
Issue number6
DOIs
Publication statusPublished - Jun 2018
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Keywords

  • Adipose Tissue/enzymology
  • Animals
  • Aromatase/biosynthesis
  • Breast/enzymology
  • Female
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Interleukin-10/metabolism
  • MAP Kinase Signaling System
  • Mammary Glands, Animal/enzymology
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1/metabolism
  • Mitogen-Activated Protein Kinase 3/metabolism
  • Tumor Necrosis Factor-alpha/metabolism

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