Rabbit Anti-Human IRF8 monoclonal antibody, clone 35I24M30

Interferon (IFN) regulatory factor 8 is encoded by a novel candidate tumor suppressor gene (IRF8), its promotor is frequently methylated in multiple cancers. However, the promoter methylation status, functions and underlying mechanisms of IRF8 in breast cancer remain unclear. We found that IRF8 was downregulated in breast cancer cell lines and primary tumors, compared with normal breast tissues, mainly because of aberrant promoter methylation. However, its expression was not associated with pathological characteristics. Restoration of IRF8 expression suppressed cell proliferation, colony formation, 5-ethynyl-2'-deoxyuridine incorporation, cell migration and invasion, and induced apoptosis and cell cycle arrest in vitro. IRF8 also inhibited xenograft growth in nude mice in vivo. Competition with IRF8 function by IRF8 mutant (K79E) enhanced cell migration and invasion in 4T1 murine cells in vitro. Importantly, IRF8, as both downstream target gene and regulator of IFN-(Upsilon)/STAT1 signaling, inhibited canonical beta-catenin signaling. These findings identify IRF8 as a novel tumor suppressor regulating IFN-(Upsilon)/STAT1 signaling and beta-catenin signaling in breast cancer.

Alterations in DNA methylation patterns in peripheral blood leukocytes precede atherosclerotic lesion development in mouse models of atherosclerosis and have been linked to cardiovascular death in patients. The aim of this study is to investigate the long-term changes induced by WTD feeding on BM cells and the consequences for atherosclerosis susceptibility. Hereto, WTD BM or Chow BM was transplanted into LDLR KO mice on chow. BM from WTD BM recipient mice exhibited hypomethylation of CpG regions in the genes encoding Pu. 1 and IRF8, key regulators of monocyte proliferation and macrophage differentiation. In agreement, in blood, the numbers of leukocytes were 40% (P<0.05) higher as a result of an increase in F4/80(+) monocytes (3.4-fold; P<0.01). An increase of CD11c(++) cells was also found (2.4-fold; P<0.05). Furthermore, spleens were enlarged, and the percentage of F4/80(+) cells expressing CD86 was induced (1.8-fold; P<0.01), indicating increased activation of splenic macrophages. Importantly, mice reconstituted with WTD BM showed a significant, 1.4-fold (P<0.05) increase in aortic root plaque size in the absence of changes in serum cholesterol. We conclude that WTD challenge induces transplantable epigenetic changes in BM, alterations in the hematopoietic system, and increased susceptibility to atherosclerosis. Manipulation of the epigenome, when used in conjunction with blood lipid reduction, could thus prove beneficial to treat cardiovascular disorders.