title: Macrophage colony stimulating factor regulation by nuclear factor kappa B: a relevant pathway in human immunodeficiency virus type 1 infected macrophages.
abstract: Macrophage colony stimulating factor (M-CSF) is a cytokine that promotes monocyte differentiation and survival. When overexpressed, M-CSF contributes to pathology in a wide variety of diseases, including osteoporosis, obesity, certain human cancers, and in human immunodeficiency virus type 1 (HIV-1) infection, particularly with respect to monocyte/macrophage infection and the development of HIV-1 associated central nervous system disorders. In this study, our aim was to expand the current knowledge of M-CSF regulation, focusing on nuclear factor kappa B (NF-κB), a transcription factor playing a prominent role during inflammation and HIV-1 infection. Our results suggest that tumor necrosis factor alpha (TNF-α) promotes M-CSF secretion in primary macrophages and activates the -1310/+48 bp M-CSF promoter in Mono-Mac 1 cells. Inhibitors of the NF-κB pathway diminish this response. We identified four putative NF-κB and four CCAAT-enhancer-binding protein beta binding sites within the M-CSF promoter. Our findings, using promoter constructs mutated at individual NF-κB sites within the M-CSF promoter region, suggest that these sites are redundant with respect to NF-κB regulation. TNF-α treatment promoted NF-κB p65 binding to the M-CSF promoter in phorbol 12-myristate 13-acetate (PMA) treated U937 cells chronically infected with HIV-1 (U1 cells), but not in PMA treated uninfected U937 cells, suggesting that the presence of HIV-1 increases the NF-κB response. In conclusion, our findings demonstrate that NF-κB induces M-CSF expression on a promoter level via multiple functional NF-κB binding sites and that this pathway is likely relevant in HIV-1 infection of macrophages.
authors: Department of Neuroscience, Center for Neurovirology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA.
authors: Michael
authors: M
authors: Kogan
authors: Valerie
authors: V
authors: Haine
authors: Yuxong
authors: Y
authors: Ke
authors: Brian
authors: B
authors: Wigdahl
authors: Tracy
authors: T
authors: Fischer-Smith
authors: Jay
authors: J
authors: Rappaport
mesh_terms: D002478:Cells, Cultured; D005786:Gene Expression Regulation; D015497:HIV-1; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D016328:NF-kappa B; D016173:Macrophage Colony-Stimulating Factor