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PMID: 12368905 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor.

Nature medicine ·Vol. 8 ·No. 11 ·2002-11-00 ·Pages 1296-302

Perretti M, Chiang N, La M, Fierro IM, Marullo S, Getting SJ, Solito E, Serhan CN

Abstract

Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A(4) receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.

MeSH Terms
Animals Anti-Inflammatory Agents/pharmacology Aspirin/pharmacology Cell Line Cells, Cultured Dexamethasone/pharmacology Humans In Vitro Techniques Lipid Metabolism Mice Molecular Sequence Data Neutrophil Activation Peptides/metabolism Receptors, Cell Surface/agonists Receptors, Formyl Peptide Receptors, Lipoxin
Chemicals
Anti-Inflammatory Agents FPR2 protein, human Peptides Receptors, Cell Surface Receptors, Formyl Peptide Receptors, Lipoxin Dexamethasone Aspirin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Perretti Mauro
[1] Department of Biochemical Pharmacology, William Harvey Research Institute, Bart's and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, UK [2] M.P. and N.C. contributed equally to this paper.
Chiang Nan
La Mylinh
Fierro Iolanda M
Marullo Stefano
Getting Stephen J
Solito Egle
Serhan Charles N
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1078-8956
DOI
10.1038/nm786
Published
2002-11-00
Epub
2002-00-07
Pages
1296-302
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2777269
Subset
IM
Grants
NIGMS NIH HHS · GM38765 · United States
Arthritis Research UK · 15755 · United Kingdom
NIGMS NIH HHS · R01 GM038765 · United States
NIDCR NIH HHS · P01-DE13499 · United States
NIDCR NIH HHS · P01 DE013499 · United States
NIGMS NIH HHS · R37 GM038765 · United States
Databases
GENBANK
U81501
External Links
PubMed source DOI: 10.1038/nm786 PMC Full Text View journal details
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