期刊
JOURNAL OF IMMUNOLOGY
卷 189, 期 4, 页码 1946-1954出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201064
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资金
- Ministerio de Economia y Competitividad [BFU2008-01493-BMC, SAF2011-23801]
- Genoma Espana
- Instituto de Salud Carlos III (Spanish Network for the Research in Infectious Diseases) [RD06/0008]
- Instituto de Salud Carlos III (Red de Investigacion en SIDA) [RD06/0006/1016]
- Comunidad Autonoma de Madrid/Fondo Europeo de Desarrollo Regional
- Ministerio de Ciencia e Innovacion [SAF2010-1602]
- European Community's Seventh Framework Programme [229673]
- Instituto de Salud Carlos III [CD09/00386]
Modulation of macrophage polarization underlies the onset and resolution of inflammatory processes, with polarization-specific molecules being actively sought as potential diagnostic and therapeutic tools. Based on their cytokine profile upon exposure to pathogenic stimuli, human monocyte-derived macrophages generated in the presence of GM-CSF or M-CSF are considered as proinflammatory (M1) or anti-inflammatory (M2) macrophages, respectively. We report in this study that the prolyl hydroxylase PHD3-encoding EGLN3 gene is specifically expressed by in vitro-generated proinflammatory M1(GM-CSF) human macrophages at the mRNA and protein level. Immunohistochemical analysis revealed the expression of PHD3 in CD163(+) lung macrophages under basal homeostatic conditions, whereas PHD3(+) macrophages were abundantly found in tissues undergoing inflammatory responses (e.g., Crohn's disease and ulcerative colitis) and in tumors. In the case of melanoma, PHD3 expression marked a subset of tumor-associated macrophages that exhibit a weak (e.g., CD163) or absent (e.g., FOLR2) expression of typical M2-polarization markers. EGLN3 gene expression in proinflammatory M1(GM-CSF) macrophages was found to be activin A dependent and could be prevented in the presence of an anti-activin A-blocking Ab or inhibitors of activin receptor-like kinase receptors. Moreover, EGLN3 gene expression was upregulated in response to hypoxia only in M2(M-CSF) macrophages, and the hypoxia-mediated upregulation of EGLN3 expression was significantly impaired by activin A neutralization. These results indicate that EGLN3 gene expression in macrophages is dependent on activin A both under basal and hypoxic conditions and that the expression of the EGLN3-encoded PHD3 prolyl hydroxylase identifies proinflammatory macrophages in vivo and in vitro. The Journal of Immunology, 2012, 189: 1946-1954.
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