Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Aditya Ambade, Abhishek Satishchandran, Banishree Saha, Benedek Gyongyosi, Patrick Lowe, Karen Kodys, Donna Catalano, G. Szabó

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat–high cholesterol–high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFα (M1) and CD163/CD206 (M2) expression using flow cytometry. Role of hif-1α-induced IL-10 was dissected in hepatocyte specific hif-1αKO and hif-1αdPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN + HF–HC–HSD mice compared to controls. Western diet resulted in macrophage (F4/80+CD11b+) infiltration to liver and DEN + HF–HC–HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1α, and livers from hif-1α over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1α and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1α in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1α mediated IL-10 polarizing M2 macrophages.

Original languageEnglish
JournalOncoImmunology
Volume5
Issue number10
DOIs
Publication statusPublished - Oct 2 2016

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Interleukin-10
Hepatocellular Carcinoma
Macrophages
Nitrosamines
Hepatocytes
Liver
Carcinogens
Neoplasms
Up-Regulation
Cytokines
Palmitic Acid
Interleukin-12
Serum
Liver Cirrhosis
Histology
Flow Cytometry
Triglycerides
Transcription Factors
Obesity
Diet

Keywords

  • CD163
  • DEN
  • epithelial-mesenchymal transition
  • M2c macrophages
  • palmitic acid

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10. / Ambade, Aditya; Satishchandran, Abhishek; Saha, Banishree; Gyongyosi, Benedek; Lowe, Patrick; Kodys, Karen; Catalano, Donna; Szabó, G.

In: OncoImmunology, Vol. 5, No. 10, 02.10.2016.

Research output: Contribution to journalArticle

Ambade, Aditya ; Satishchandran, Abhishek ; Saha, Banishree ; Gyongyosi, Benedek ; Lowe, Patrick ; Kodys, Karen ; Catalano, Donna ; Szabó, G. / Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10. In: OncoImmunology. 2016 ; Vol. 5, No. 10.
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