title: Characterization of the promoter and the transcriptional regulation of the lipoxin A4 receptor (FPR2/ALX) gene in human monocytes and macrophages.
abstract: The lipoxin A4 receptor FPR2/ALX plays an important part in host defense and inflammation. The receptor binds structurally diverse agonistic ligands, which mainly regulate chemotaxis and activation of leukocytes. However, little is known about the promoter region of the FPR2/ALX gene and its transcriptional regulation in leukocytes. We identified two TATA-less promoter regions, separated by 224 bp, that drive the expression of FPR2/ALX in macrophages. Both promoter regions increased transcription in a reporter assay, and the basal transcription factors OCT1 and SP1 were shown to bind the first and the second promoter, respectively, and to transactivate transcription. Although monocytes expressed high levels of FPR2/ALX mRNA from the second promoter region, differentiation into macrophages abrogated FPR2/ALX expression. Stimulation of macrophages with a set of cytokines revealed that only IFN-γ and LPS increased FPR2/ALX expression from the first promoter to levels similar to those detected in monocytes. The upregulation by IFN-γ is in part mediated by the interaction of IFN regulatory factor 1 with an IFN-responsive sequence element transcription factor binding site located in the first promoter region of the FPR2/ALX gene. However, this upregulation on the mRNA level did not translate into FPR2/ALX protein expression in macrophages owing to reduced translation of the longer mRNA from the first promoter. In contrast, FPR2/ALX mRNA transcribed from the second promoter was translated into surface expression of FPR2/ALX in monocytes. These data support a model in which FPR2/ALX plays a role in chemotaxis and activation of monocytes; however, they also suggest that its function in resident tissue macrophages is limited.
authors.affiliation: Division of Clinical Chemistry and Biochemistry, Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Waechter
authors.forename: Mattia
authors.initials: M
authors.lastname: Schmid
authors.forename: Magdalena
authors.initials: M
authors.lastname: Herova
authors.forename: Angelika
authors.initials: A
authors.lastname: Weber
authors.forename: Viola
authors.initials: V
authors.lastname: Günther
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marti-Jaun
authors.forename: Sophia
authors.initials: S
authors.lastname: Wüst
authors.forename: Marian
authors.initials: M
authors.lastname: Rösinger
authors.forename: Claudio
authors.initials: C
authors.lastname: Gemperle
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D044042:Receptors, Formyl Peptide / Q000235:genetics* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D020121:5' Untranslated Regions; C105101:FPR2 protein, human; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D027702:Organic Cation Transporter 1; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D016329:Sp1 Transcription Factor; D007371:Interferon-gamma