Lipoxin A₄ and serum amyloid a differentially modulate phospholipase D in human fibroblast-like synoviocytes

Lipoxin A₄ (LXA₄) and serum amyloid A (SAA) are endogenous negative and positive modulators of inflammation, respectively. Both molecules bind the shared lipoxin A₄ receptor (ALX) and elicit opposing effects on the production of inflammatory cytokines and matrix metalloproteinases. The aim of these studies is to examine the divergence of the intracellular signaling pathways triggered by lipid LXA₄ (1 nM) and protein SAA (200 nM) ligands of ALX. Phospholipase D (PLD) is a phosphohydrolase enzyme that catalyzes the generation of phosphatidic acid (PA) from membrane phospholipids. Our results showed that in fibroblast-like synoviocytes, activation of PLD occurred only in response to LXA₄, and not SAA. PA (30 μM) mimicked LXA₄ and demonstrated inhibition of IL-8 production induced by SAA or interleukin-1β. In sharp contrast to LXA₄, SAA confirmed the stimulation of IL-8 release as determined previously. Taken together, these findings suggest that two physiologic ligands sharing the common ALX receptor, LXA₄ and SAA, differentially regulate the level of PLD activation and differentially modulate IL-8. These results may have important implications for understanding the regulation of inflammatory responses under physiologic and pathological conditions.