Opposing regulation of interleukin-8 and NF-kB responses by lipoxin A4 and serum amyloid a via the common lipoxin a receptor

S. Sodin-Semrl, A. Spagnolo, R. Mikus, B. Barbaro, J. Varga, Stefano Fiore*

*Corresponding author for this work

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Lipoxin A4(LXA4) is a potent eicosanoid that inhibits IL-1β-induced activation of human fibroblast-like synoviocytes (FLS) via the LXA4 receptor (ALXR). Serum amyloid A (SAA) is an acute phase reactant with cytokine-like properties. SAA has been shown to bind the same seven transmembrane G protein-coupled receptor ligated by LXA4. Here we compared the inflammatory responses of lipid (LXA4) and peptide (SAA) ligands in human FLS via the shared ALX and characterized their downstream signaling. LXA4 induced stimulation of tissue inhibitors of metalloproteinase-2, whereas SAA induced interleukin-8 and matrix metalloproteinase-3 production. SAA up-regulated NF-kB and AP-1 DNA binding activity, while LXA4 markedly inhibited these responses after IL-1β stimulation. A human IL-8 promoter luciferase construct was transfected into CHO cells stably expressing ALXR in order to determine the role of NF-kB and/or AP-1 in the regulation of IL-8 gene expression. The NF-kB pathway proved to be the preeminent for the biological responses elicited by both ligands. These findings suggest that two endogenous molecules, targeting a common receptor, could participate in the pathogenesis of inflammatory arthritis by differentially regulating inflammatory responses in tissues expressing the ALXR.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalInternational journal of immunopathology and pharmacology
Volume17
Issue number2
DOIs
StatePublished - Jan 1 2004

Keywords

  • Acute-phase reactants
  • Cytokines
  • Inflammation
  • Lipid mediators
  • Transcription factors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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