title: Downstream gene activation of the receptor ALX by the agonist annexin A1.
abstract: BACKGROUND
  Our understanding of pro-resolution factors in determining the outcome of inflammation has recently gained ground, yet not many studies have investigated whether specific genes or patterns of genes, are modified by these mediators. Here, we have focussed on the glucocorticoid modulated pro-resolution factor annexin A1 (AnxA1), studying if its interaction with the ALX receptor would affect downstream genomic targets.
  
  
  RESULTS
  Using microarray technology in ALX transfected HEK293 cells, we discovered an over-lapping, yet distinct gene activation profile for AnxA1 compared to its N-terminal mimetic peptide Ac2-26, which may be suggestive of unique downstream inflammatory outcomes for each substance. When the up-regulated genes were explored, consistently induced was the sphingosine phosphate phosphatase-2 gene (SGPP2), involved in regulation of the sphingosine 1 phosphate chemotactic system. Up-regulation of this gene, as well as JAG1 (and down-regulation of JAM3), was confirmed using real time PCR both with transfected HEK293 cells and human peripheral blood leukocytes. Furthermore, lymph nodes taken from AnxA1(null) mice displayed lower SGPP2 gene activity. Finally, connectivity map analysis for AnxA1 and peptide Ac2-26 indicated striking similarities with known anti-inflammatory therapeutics, glucocorticoids and aspirin-like compounds, as well as with histone deacetylase inhibitors.
  
  
  CONCLUSIONS
  We believe these new data raise the profile of AnxA1 from being solely a short-term anti-inflammatory factor, to being a 'trigger' of the endogenous pro-resolution arsenal.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Renshaw
authors.forename: Trinidad
authors.initials: T
authors.lastname: Montero-Melendez
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kamal
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brancaleone
authors.forename: Fulvio
authors.initials: F
authors.lastname: D'Acquisto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017305:Annexin A1; C442142:HSH2D protein, human; D008565:Membrane Proteins; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases