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Role of lipoxins, antiflammins and serum amyloid A signaling via the common ALXR receptor in joint tissue inflammation

Serum amyloid A (SAA) is an acute-phase protein and inflammatory marker of rheumatoid arthritis, which has recently become recognized as a cytokine-like reactant. SAA has been shown to bind to the ALXR (FPRL1/LXA4R) receptor and to elicit proinflammatory activities. Indeed, we have determined that SAA elicits the proinflammatory activation of human fibroblast-like synoviocytes, with a profile of activity similar to that of IL-1β. Uteroglobin is a ubiquitously expressed secretory protein with anti-inflammatory properties that shares specific sequence motifs with annexin-1, a steroid-induced anti-inflammatory peptide that is also capable of interacting with ALXR. Data obtained by flow cytometry, ELISA and plasmon resonance, using ALXR stably transfected CHO cells, suggest that uteroglobin can downmodulate SAA proinflammatory effects by specifically interfering at the ALXR receptor level. In agreement with the ability to bind to the same receptor used by SAA, a functional antagonism between uteroglobin and SAA was observed, with uteroglobin causing inhibition of SAA-induced release of both IL-8 and IL-6, and blockage of SAA-induced PLA2 activation. Beside the receptor antagonism between proinflammatory ALXR ligands (SAA, urokinase proteolytic plasminogen peptides [uPA], MK1, etc.) and anti-inflammatory ALXR ligands (LXA4, annexin-1, uteroglobin) so far identified, results also suggest that each of these mediators can modify ALXR expression levels as well as other genes. In fact, present studies suggest that SAA acts in a positive autoregulatory feedback mechanism by increasing SAA 1 + 2 expression, while maintaining unchanged levels of its constitutively expressed isoform SAA4, as demonstrated by RT-PCR. Following SAA treatment, upregulation is extended to the expression of the ALXR mRNA, a response common to LXA4 and IL-1β. The antagonistic activities of SAA, uPA, uteroglobin, annexin-1 and LXA4 might constitute a novel complex signaling mechanism by which these mediators sharing a common receptor could achieve opposing roles in the regulation of the joint inflammatory processes.

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Fiore, S., Sodin-Semrl, S., Antico, G. et al. Role of lipoxins, antiflammins and serum amyloid A signaling via the common ALXR receptor in joint tissue inflammation. Arthritis Res Ther 5 (Suppl 3), 69 (2003).

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