The lipoxin A₄ receptor (ALXR) is expressed in fibroblast-like synoviocytes and is targeted by both antiinflammatory and proinflammatory endogenous ligands. Recently, annexin-1 (lipocortin) has been identified to be an ALXR ligand. Uteroglobin (Ug) is secretoglobin that shares with annexin-1 properties such as potent inhibition of phospholipase A₂ (PLA₂) as well as sequence similarities in the 'antiflammin' consensus region. Potential receptor interactions of Ug with ALXR were therefore investigated and PLA₂ activity assays were performed in CHO and HL-60 cell lines stably overexpressing ALXR. Serum amyloid A (SAA), an ALXR ligand displaying proinflammatory activities, was compared with two antiinflammatory ligands, Ug and lipoxin A₄ (LXA₄). While Ug and LXA₄ did not alter baseline PLA₂ activity (Ug) or provoked a pulsed peak of activity (LXA₄), SAA did induce a delayed and prolonged activation of PLA₂. SAA-induced PLA₂activation was sharply inhibited in the presence of Ug. Ug inhibition of SAA-dependent phospholipase activity occurred at submillimolar Ca²⁺ concentrations, suggesting an effect on cytosolic PLA₂ (rather than secretory PLA₂, a known target inhibited by Ug and annexin-1 but requiring millimolar Ca²⁺). Studies of Erk, p38 and AKT kinase phosphorylation confirmed that SAA and Ug interact with ALXR to oppositely regulate GPCR-coupled downstream signaling events. Overall the analysis of phospholipase D activity, kinase phosphorylation and cAMP levels also suggested that proinflammatory and antiinflammatory ligands of ALXR engage differently coupled pathways, leading to activation of these processes (SAA) or to their inhibition (LXA₄ and Ug). These signaling events are functionally matched by the ability of SAA to stimulate NF-κB activity, IL-8 release and cell chemotaxis, and that of LXA₄ and Ug to strongly inhibit them. Expression of Ug and SAA mRNAs was also detected in human fibroblast-like synoviocytes, suggesting that ALXR may play a pivotal role in the pathophysiology of arthritis. In addition, annexin-1 and Ug inhibition of PLA₂ offers enticing new venues to control inflammatory arthritides by limiting, for example, cascade signaling amplification via synthesis of proinflammatory eicosanoids, along with a redirection of ALXR signaling toward antiinflammatory feedback mechanisms.