Exaggerated activation of leukocyte immune functions in rheumatoid arthritis (RA) leads to accumulation of inflammatory mediators. The resulting imbalance, with prevalence of inflammatory Thl1 cytokines, contributes to chronic inflammation and tissue damage. A significant role in these processes has been attributed to the recruitment of tissue components, such as the synovial cell lining. For example, cytokine-induced activation of synovial fibroblasts amplifies the cytokine signaling cascade and the release of matrix-degrading enzymes. This contributes to the destructive processes occurring in RA joints. We hypothesize that lipoxins (LX), a novel class of naturally occurring lipid mediators with marked anti-inflammatory actions, activate feedback mechanisms that prevent the exaggerated amplification of these inflammatory processes. We have previously elucidated and cloned a specific LX receptor (LXA4R) that mediates LX anti-inflammatory actions in leukocytes. We recently found that LX functional receptors are expressed in human (hLX! R) and mouse (mLXA4R) synovial fibroblasts. We propose to determine if expression of LXA4R will subject synovial fibroblasts to LX regulatory activities. This goal will be pursue by: 1) characterizing, at the molecular and functional level, LXA4 signaling pathways in synovial fibroblasts; and 2) assessing LXA4 regulatory actions toward cytokine-induced activation of synovial fibroblasts. Since, a decrease of the Th2/Th1 cytokines ratio is observed in RA, and Th2 cytokines positively regulate 15-LO gene transcription, a third Aim will evaluate synovial fibroblast 15-lipoxygenase (15-LO) pathway and LX biosynthetic potential. Decreased 15-LO activity can negatively impact the synthesis of 15-LO derived anti-inflammatory eicosanoids, such as LX and 15-hydroxy derivatives of arachidonic acid. Therefore, elucidation of cytokine-dependent regulation-of 15-LO pathways in synovium will elucidate 15-LO pathways and generated mediators in negative feedback loops relevant to the pathophysiology of RA and offer new targets for novel therapeutic strategies. Finally the biology and therapeutic potential of LX will be investigated in twomouse models of inflammatory arthritis: the antigen-induced and the proteoglycan-induced models.
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