TRANSCRIPTIONAL REGULATION OF LYSOSOMAL ACID LIPASE IN DIFFERENTIATING MONOCYTES IS MEDIATED BY TRANSCRIPTION FACTORS SP1 AND AP-2

Human lysosomal acid lipase (LAL) is a hydrolase required for the clea vage of cholesteryl esters and triglycerides derived from plasma lipop roteins. It is shown here that during monocyte to macrophage different iation, the expression of LAL-mRNA is induced. This induction is depen dent on protein kinase C activity and protein synthesis. The cell type -specific increase in LAL expression is further investigated in the TH P-1 cell line with respect to transcriptional regulation. The human mo nocytic leukemia cell line THP-1 differentiates into macrophage-like c ells when treated with phorbol esters. In order to determine the cis-a cting elements necessary for both basal and phorbol 12-myristate-13 ac etate (PMA)-enhanced promoter activity, we performed deletion analysis and reporter gene assays. A PMA responsive element has been identifie d between -182 bp and -107 bp upstream of the major transcription star t site. Gel mobility shift assays demonstrated that binding of Spl and AP-2 to the LAL promoter is increased by PMA in THP-1 cells. Co-trans fections with expression plasmids for Sp1 and AP-2 further emphasized the important role of these transcription factors in both basal and PM A-enhanced LAL expression.jlr Our data suggest that differentiation de pendent increase of lysosomal acid lipase (LAL) expression in THP-I ce lls is mediated by a concerted action of Sp1 and AP-2.