Genetic determination of the role of PU.1 in macrophage gene expression.

Joo M, Kwon M, Azim AC, Sadikot RT, Blackwell TS, Christman JW
Biochem Biophys Res Commun. 2008 372 (1): 97-102

PMID: 18485892 · PMCID: PMC2494535 · DOI:10.1016/j.bbrc.2008.04.189

PU.1, an Ets family transcription factor, mediates macrophage effector function in inflammation by regulating gene expression. But, the extent and nature of PU.1 function in gene expression has not been genetically determined because ablation of PU.1 gene abolishes macrophage development. Here, we epigenetically suppressed PU.1 by stably expressing PU.1 specific siRNA in macrophages, and determined the effect of PU.1 deficiency on expressions of key inflammatory genes: Toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX-2), and macrophage inflammatory protein-1alpha (MIP-1alpha). PU.1-silenced cell lines expressed lower TLR4 mRNA and COX-2 protein, but higher MIP-1alpha protein, than controls. Over-expression of PU.1 suppressed lipopolysaccharide-induced MIP-1alpha production. PU.1 occupied proximal and distal cognate sites in the endogenous MIP-1alpha promoter, but dissociated only from the distal sites in response to lipopolysaccharide, suggesting a novel negative regulatory mechanism by PU.1. Together, our results defined PU.1 function in differentially regulating expressions of TLR4, COX-2, and MIP-1alpha.

MeSH Terms (12)

Animals Cell Line Chemokine CCL3 Cyclooxygenase 2 Gene Expression Regulation Macrophages Mice Proto-Oncogene Proteins RNA, Messenger Toll-Like Receptor 4 Trans-Activators Up-Regulation

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