Opposing Regulation of Interleukin-8 and NF-kB Responses by Lipoxin A4 and Serum Amyloid a via the Common Lipoxin a Receptor

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.