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Autophagy. 2013 Apr;9(4):619-21. doi: 10.4161/auto.23546. Epub 2013 Jan 29.

Targeting NFKB by autophagy to polarize hepatoma-associated macrophage differentiation.

Author information

  • 1Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. cpchang@mail.ncku.edu.tw

Abstract

Tumor-associated macrophages (TAMs) have been linked to promoting tumor progression by stimulating angiogenesis, cell growth and inflammation. NFKB activity in TAMs may mediate inflammation-associated tumor formation. However, most isolated TAMs from established tumors express a M2 phenotype with less NFKB activation and show a strong immunosuppressive phenomenon. How tumors affect the dynamic of NFKB activity in TAMs, and hence maintain their pro-tumor M2 phenotype is still poorly understood. We recently found that hepatoma-derived toll-like receptor 2 (TLR2)-related ligands are capable of stimulating M2 macrophage differentiation via controlling NFKB RELA/p65 protein homeostasis by selective autophagy. TLR2 signal induces NFKB RELA cytosolic ubiquitination and leads to its degradation by SQSTM1/p62-mediated autophagy. Inhibition of autophagy will rescue NFKB activity and shape the phenotype of hepatoma-polarized M2 macrophages. This suggests that autophagy might play a role in manipulating TAM functions and tumor-associated immune responses. Our study also demonstrates that autophagy can directly control a transcriptional factor in addition to its regulatory molecules. This finding uncovers a new role of autophagy in controlling cellular functions.

KEYWORDS:

NFKB; SQSTM1/p62; TLR2; selective autophagy; tumor-associated macrophages

PMID:
23360732
[PubMed - indexed for MEDLINE]
PMCID:
PMC3627680
Free PMC Article
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