Macrophage Colony Stimulating Factor Regulation by Nuclear Factor Kappa B: A Relevant Pathway in Human Immunodeficiency Virus Type 1 Infected Macrophages

作者：Kogan Michael; Haine Valerie; Ke Yuxong; Wigdahl Brian; Fischer Smith Tracy; Rappaport Jay^*

来源：DNA and Cell Biology, 2012, 31(3): 279-288.

DOI：10.1089/dna.2011.1357

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-kappa B), a transcription factor playing a prominent role during inflammation and HIV-1 infection. Our results suggest that tumor necrosis factor alpha (TNF-alpha) 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-kappa B pathway diminish this response. We identified four putative NF-kappa B and four CCAAT-enhancer-binding protein beta binding sites within the M-CSF promoter. Our findings, using promoter constructs mutated at individual NF-kappa B sites within the M-CSF promoter region, suggest that these sites are redundant with respect to NF-kappa B regulation. TNF-alpha treatment promoted NF-kappa B 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-kappa B response. In conclusion, our findings demonstrate that NF-kappa B induces M-CSF expression on a promoter level via multiple functional NF-kappa B binding sites and that this pathway is likely relevant in HIV-1 infection of macrophages.

• 出版日期2012-3