Downstream gene activation of the receptor ALX by the agonist annexin A1.
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.
Renshaw
Derek
D
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
Montero-Melendez
Trinidad
T
Dalli
Jesmond
J
Kamal
Ahmad
A
Brancaleone
Vincenzo
V
D'Acquisto
Fulvio
F
Cirino
Giuseppe
G
Perretti
Mauro
M
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
D048868:Adaptor Proteins, Signal Transducing; D017305:Annexin A1; C442142:HSH2D protein, human; D008565:Membrane Proteins; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases