TY - JOUR
T1 - Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology
AU - Pello, Oscar M.
AU - De Pizzol, Maria
AU - Mirolo, Massimiliano
AU - Soucek, Laura
AU - Zammataro, Luca
AU - Amabile, Angelo
AU - Doni, Andrea
AU - Nebuloni, Manuela
AU - Swigart, Lamorna B.
AU - Evan, Gerard I.
AU - Mantovani, Alberto
AU - Locati, Massimo
PY - 2012/1/12
Y1 - 2012/1/12
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-02-339911
DO - 10.1182/blood-2011-02-339911
M3 - Article
C2 - 22067385
AN - SCOPUS:84855846598
SN - 0006-4971
VL - 119
SP - 411
EP - 421
JO - Blood
JF - Blood
IS - 2
ER -