Downstream gene activation of the receptor ALX by the agonist Annexin A1

Renshaw, D., Montero-Melendez, T., Dalli, J., Kamal, A., Brancaleone, V., D'Acquisto, F., Cirino, G. and Perretti, M. 2010. Downstream gene activation of the receptor ALX by the agonist Annexin A1. PLoS ONE. 5 (9) e12771. https://doi.org/10.1371/journal.pone.0012771

TitleDownstream gene activation of the receptor ALX by the agonist Annexin A1
TypeJournal article
AuthorsRenshaw, D., Montero-Melendez, T., Dalli, J., Kamal, A., Brancaleone, V., D'Acquisto, F., Cirino, G. and Perretti, M.
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.

Methodology/Principal Findings

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 AnxA1null 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.

Conclusion/Significance

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.

Article numbere12771
JournalPLoS ONE
Journal citation5 (9)
ISSN1932-6203
Year2010
PublisherPublic Library of Science
Digital Object Identifier (DOI)https://doi.org/10.1371/journal.pone.0012771
Publication dates
Published17 Sep 2010

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Getting, S.J., Lam, C.W., Leoni, G., Gavins, F.N.E., Grieco, P. and Perretti, M. 2006. [D -Trp8]-γ -melanocyte -stimulating hormone exhibits anti-inflammatory efficacy in mice bearing a nonfunctional MC1 R(Recessive Yellow e/e Mouse). Molecular Pharmacology. 70 (6), pp. 1850-1855. https://doi.org/10.1124/mol.106.028878

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Schwarz, N., Renshaw, D., Kapas, S. and Hinson, J.P. 2006. Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells. Journal of Endocrinology. 190 (2), pp. 505-514. https://doi.org/10.1677/joe.1.06806

Intra-adrenal mechanisms in the response to chronic stress: investigation in a rat model of emotionality
Kosti, O., Raven, P.W., Renshaw, D. and Hinson, J.P. 2006. Intra-adrenal mechanisms in the response to chronic stress: investigation in a rat model of emotionality. Journal of Endocrinology. 189 (2), pp. 211-218. https://doi.org/10.1677/joe.1.06638

Melanocortin receptor signaling in RAW264.7 macrophage cell line
Lam, C.W., Perretti, M. and Getting, S.J. 2006. Melanocortin receptor signaling in RAW264.7 macrophage cell line. Peptides. 27 (2), pp. 404-412. https://doi.org/10.1016/j.peptides.2005.01.031

The melanocortin peptide HP228 displays protective effects in acute models of inflammation and organ damage
Getting, S.J., Di Filippo, C., D'Amico, M. and Perretti, M. 2006. The melanocortin peptide HP228 displays protective effects in acute models of inflammation and organ damage. European Journal of Pharmacology. 532 (1-2), pp. 138-144. https://doi.org/10.1016/j.ejphar.2005.12.023

Melanocortin 3 receptors control crystal-induced inflammation
Getting, S.J., Lam, C.W., Chen, A.S., Grieco, P. and Perretti, M. 2006. Melanocortin 3 receptors control crystal-induced inflammation. FASEB Journal. 20 (13), pp. 2234-2241.

In vitro and in vivo induction of heme oxygenase 1 in mouse macrophages following melanocortin receptor activation
Lam, C.W., Getting, S.J. and Perretti, M. 2005. In vitro and in vivo induction of heme oxygenase 1 in mouse macrophages following melanocortin receptor activation. Journal of Immunology. 174 (4), pp. 2297-2304.

MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct
Getting, S.J., Di Filippo, C., Christian, H.C., Lam, C.W., Rossi, F., D'Amico, M. and Perretti, M. 2004. MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct. Journal of Leukocyte Biology. 76 (4), pp. 845-853. https://doi.org/10.1189/jlb.0306175

The annexin 1-/- mouse: phenotypic studies
Wells, D., Wells, K., Liu, K., Hannon, R., Croxtall, J.D., Damazo, A.S., Oliani, S.M., Getting, S.J., Parente, L., Paul-Clark, M., Yona, S., Gavins, F.N.E., Martin, J., Christian, H.C., Cover, P.O., John, C.D., Solito, E., Morris, J.F., Perretti, M., Buckingham, J.C. and Flower, R.J. 2004. The annexin 1-/- mouse: phenotypic studies. Annexins. 1 (2), pp. 109-120.

Activation of melanocortin receptors induces cAMP-dependent hemeoxygenase-1 expression in murine macrophages
Lam, C.W., Getting, S.J. and Perretti, M. 2004. Activation of melanocortin receptors induces cAMP-dependent hemeoxygenase-1 expression in murine macrophages. pA2 Online. Winter 2004 Meeting: Proceedings of the British Pharmacological Society.

Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides
Getting, S.J., Schiöth, H.B. and Perretti, M. 2003. Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides. Journal of Pharmacology and Experimental Therapeutics. 306 (2), pp. 631-637. https://doi.org/10.1124/jpet.103.051623

Redundancy of a Functional Melanocortin 1 Receptor in the Anti-inflammatory actions of melanocortin peptides: studies in the recessive yellow (e/e) mouse suggest an important role for melanocortin 3 receptor
Getting, S.J., Christian, H.C., Lam, C.W., Gavins, F.N.E., Flower, R.J., Schiöth, H.B. and Perretti, M. 2003. Redundancy of a Functional Melanocortin 1 Receptor in the Anti-inflammatory actions of melanocortin peptides: studies in the recessive yellow (e/e) mouse suggest an important role for melanocortin 3 receptor. Journal of Immunology. 170 (6), pp. 3323-3330.

Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse
Hannon, R., Croxtall, J.D., Getting, S.J., Roviezzo, F., Yona, S., Paul-Clark, M., Gavins, F.N.E., Perretti, M., Morris, J.F., Buckingham, J.C. and Flower, R.J. 2003. Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse. FASEB Journal. 17 (2), pp. 253-255. https://doi.org/10.1096/fj.02-0239fje

Migration of specific leukocyte subsets in response to cytokine or chemokine application in vivo
Perretti, M. and Getting, S.J. 2003. Migration of specific leukocyte subsets in response to cytokine or chemokine application in vivo. Methods in Molecular Biology. 225, pp. 139-146. https://doi.org/10.1385/1-59259-374-7:139

Migration of specific leukocyte sub-sets in response to cytokine or chemokine application in vivo
Perretti, M. and Getting, S.J. 2003. Migration of specific leukocyte sub-sets in response to cytokine or chemokine application in vivo. in: Winyard, P.G. and Willoughby, D.A. (ed.) Inflammation Protocols Totowa, NJ Humana Press. pp. 139-146

The link module from human TSG-6 inhibits neutrophil migration in a hyaluronan- and inter-alpha -inhibitor-independent manner
Getting, S.J., Mahoney, D.J., Cao, T.V., Rugg, M.S., Fries, E., Milner, C.M., Perretti, M. and Day, A.J. 2002. The link module from human TSG-6 inhibits neutrophil migration in a hyaluronan- and inter-alpha -inhibitor-independent manner. Journal of Biological Chemistry. 277 (52), pp. 51068-51076. https://doi.org/10.1074/jbc.M205121200

The annexin-1 knockout mouse: what it tells us about the inflammatory response
Roviezzo, F., Getting, S.J., Paul-Clark, M., Yona, S., Gavins, F.N.E., Perretti, M., Hannon, R., Croxtall, J.D., Buckingham, J.C. and Flower, R.J. 2002. The annexin-1 knockout mouse: what it tells us about the inflammatory response. Journal of Physiology and Pharmacology. 53 (4, part 1), pp. 541 -553.

Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor
Perretti, M., Chiang, N., La, M., Fierro, I.M., Marullo, S., Getting, S.J., Solito, E. and Serhan, C.N. 2002. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nature Medicine. 8 (11), pp. 1296-1302. https://doi.org/10.1038/nm786

Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis
Getting, S.J., Christian, H.C., Flower, R.J. and Perretti, M. 2002. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis & Rheumatism. 46 (10), pp. 2765-2775. https://doi.org/10.1002/art.10526

A novel control mechanism based on GDNF modulation of somatostatin release from sensory neurones
Malcangio, M., Getting, S.J., Grist, J., Cunningham, J.R., Bradbury, E.J., Issa, P.C., Lever, I.J., Pezet, S. and Perretti, M. 2002. A novel control mechanism based on GDNF modulation of somatostatin release from sensory neurones. FASEB Journal. 16 (7), pp. 730-732. https://doi.org/10.1096/fj.01-0971fje.

Characterization of CXC and CC chemokine expression in a murine model of chronic granuloma
Carollo, M., Getting, S.J., Delaney, S., Christie, M.I. and Perretti, M. 2002. Characterization of CXC and CC chemokine expression in a murine model of chronic granuloma. Inflammation Research. 51 (2), pp. 110-111. https://doi.org/10.1007/BF02684013

Bacterial lipopolysaccharide directly stimulates cortisol secretion in human adrenal cells
Vakharia, K., Renshaw, D. and Hinson, J.P. 2002. Bacterial lipopolysaccharide directly stimulates cortisol secretion in human adrenal cells. Endocrine Research. 28 (4), pp. 357-361. https://doi.org/10.1081/ERC-120016809

Regulation of rat adrenal vasoactive intestinal peptide content: effects of adrenocorticotropic hormone treatment and changes in dietary sodium intake
Hinson, J.P., Renshaw, D., Carroll, M. and Kapas, S. 2001. Regulation of rat adrenal vasoactive intestinal peptide content: effects of adrenocorticotropic hormone treatment and changes in dietary sodium intake. Journal of Neuroendocrinology. 13 (9), pp. 769-773. https://doi.org/10.1046/j.1365-2826.2001.00692.x

Involvement of the receptor for formylated peptides in the in vivo anti-migratory actions of annexin 1 and its mimetics
Perretti, M., Getting, S.J., Solito, E., Murphy, P.M. and Gao, J.L. 2001. Involvement of the receptor for formylated peptides in the in vivo anti-migratory actions of annexin 1 and its mimetics. American Journal of Pathology. 158 (6), pp. 1969-1973.

Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase
Mabley, J.G., Jagtap, P., Perretti, M., Getting, S.J., Salzman, A.L., Virag, L., Szabo, E., Soriano, F.G., Liaudet, L., Hasko, G., Marton, A., Southan, G.J., Abdelkarim, G.E. and Szabo, C. 2001. Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase. Inflammation Research. 50 (11), pp. 561-569. https://doi.org/10.1007/PL00000234

Arthritic diseases: melanocortin type 3 receptor agonists as potential therapeutics
Getting, S.J. and Perretti, M. 2001. Arthritic diseases: melanocortin type 3 receptor agonists as potential therapeutics. Current Opinion in Investigational Drugs. 2 (8), pp. 1064-1069.

Natural and synthetic agonists of the melanocortin receptor type 3 possess anti-inflammatory properties
Getting, S.J., Allcock, G.H., Flower, R.J. and Perretti, M. 2001. Natural and synthetic agonists of the melanocortin receptor type 3 possess anti-inflammatory properties. Journal of Leukocyte Biology. 69 (1), pp. 98-104.

MC3-R as a novel target for anti-inflammatory therapy
Getting, S.J. and Perretti, M. 2000. MC3-R as a novel target for anti-inflammatory therapy. Drug News & Perspectives. 13 (1), pp. 19-27.

POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation
Getting, S.J., Gibbs, L., Clark, A.J.L., Flower, R.J. and Perretti, M. 1999. POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation. Journal of Immunology. 162 (12), pp. 7446-7453.

Compounds for use in the treatment of inflammation
Flower, R.J., Getting, S.J. and Perretti, M. 1998. Compounds for use in the treatment of inflammation.

Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts anti-inflammatory effects
Szabo, C., Lim, L.H.K., Cuzzocrea, S., Getting, S.J., Zingarelli, B., Flower, R.J., Salzman, A.L. and Perretti, M. 1997. Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts anti-inflammatory effects. Journal of experimental medicine. 186 (7), pp. 1041-1049. https://doi.org/10.1084/jem.186.7.1041

Molecular determinants of monosodium urate crystal-induced murine peritonitis: a role for endogenous mast cells and a distinct requirement for endothelial-derived selectins
Getting, S.J., Flower, R.J., Parente, L., de Medicis, R., Lussier, A., Woliztky, B.A., Martins, M.A. and Perretti, M. 1997. Molecular determinants of monosodium urate crystal-induced murine peritonitis: a role for endogenous mast cells and a distinct requirement for endothelial-derived selectins. Journal of Pharmacology and Experimental Therapeutics. 283 (1), pp. 123-130.

Inhibition of neutrophil and monocyte recruitment by endogenous and exogenous lipocortin 1
Getting, S.J., Flower, R.J. and Perretti, M. 1997. Inhibition of neutrophil and monocyte recruitment by endogenous and exogenous lipocortin 1. British Journal of Pharmacology. 120 (6), pp. 1075-1082. https://doi.org/10.1038/sj.bjp.0701029

Sub-acute treatment of rats with dexamethasone reduces ICAM-1 levels on circulating monocytes
Tailor, A., Das, A.M., Getting, S.J., Flower, R.J. and Perretti, M. 1997. Sub-acute treatment of rats with dexamethasone reduces ICAM-1 levels on circulating monocytes. Biochemical and Biophysical Research Communications. 231 (3), pp. 675-678. https://doi.org/10.1006/bbrc.1997.6168

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