Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

• Published in: Blood Vol. 119; no. 2; pp. 411 - 421
• Main Authors: Pello, Oscar M., De Pizzol, Maria, Mirolo, Massimiliano, Soucek, Laura, Zammataro, Luca, Amabile, Angelo, Doni, Andrea, Nebuloni, Manuela, Swigart, Lamorna B., Evan, Gerard I., Mantovani, Alberto, Locati, Massimo
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 12.01.2012; Americain Society of Hematology
• Subjects: Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Differentiation; Cells, Cultured; Chromatin Immunoprecipitation; Colon - metabolism; Colon - pathology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Interleukin-4 - pharmacology; Macrophage Activation - drug effects; Macrophages - cytology; Macrophages - metabolism; Medical sciences; Oligonucleotide Array Sequence Analysis; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PPAR gamma - genetics; PPAR gamma - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Human; Hematology; Tumor associated macrophage; C-Onc gene; myc Gene; Biology; Protooncogene
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-02-339911

In response to microenvironmental signals, macrophages undergo different activation, including the “classic” proinflammatory phenotype (also called M1), the “alternative” activation induced by the IL-4/IL-13 trigger, and the related but distinct heterogeneous M2 polarization associated with the anti-inflammatory profile. The latter is induced by several stimuli, including IL-10 and TGF-β. Macrophage-polarized activation has profound effects on immune and inflammatory responses and in tumor biology, but information on the underlying molecular pathways is scarce. In the present study, we report that alternative polarization of macrophages requires the transcription factor c-MYC. In macrophages, IL-4 and different stimuli sustaining M2-like polarization induce c-MYC expression and its translocation to the nucleus. c-MYC controls the induction of a subset (45%) of genes associated with alternative activation. ChIP assays indicate that c-MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator–activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1α, and TGF-β. We conclude that c-MYC is a key player in alternative macrophage activation, and is therefore a potential therapeutic target in pathologies related to these cells, including tumors.