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Abstract

Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.

Patrick Marcouiller, Jean-Pierre Pelletier, Mélanie Guévremont, Johanne Martel-Pelletier, Pierre Ranger, Stefan Laufer and Pascal Reboul
The Journal of Rheumatology April 2005, 32 (4) 704-712;
Patrick Marcouiller
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Jean-Pierre Pelletier
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Mélanie Guévremont
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Johanne Martel-Pelletier
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Pierre Ranger
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Stefan Laufer
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Pascal Reboul
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Abstract

OBJECTIVE: To study the mechanisms responsible for the cross-talk between lipoxygenase (LOX) and cyclooxygenase (COX) pathways in human osteoarthritic (OA) synovial explants, and to confirm the arachidonic acid (AA) shunting phenomenon and its influence on interleukin 1beta (IL-1beta) synthesis. METHODS: Synovial membrane explants were cultured in the absence or presence of different drugs that inhibit COX and/or LOX activities. Concentrations of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), lipoxin A4 (LXA4), and IL-1beta were measured. RESULTS: When membrane explants were incubated with naproxen (COX inhibitor) under unstimulated conditions, the production of LTB4 was dose-dependently enhanced, reaching a 5-fold increase over the control. This shunt could be partially reversed by the addition of exogenous PGE2. Under lipopolysaccharide (LPS) stimulation, both licofelone (COX/LOX inhibitor) at therapeutic concentrations and NDGA (LOX inhibitor) inhibited LTB4 production, whereas naproxen did not amplify the LPS-induced LTB4 production. Conversely, using NDGA, it was found that a shunt of AA from the LOX to the COX pathway did not occur. Under LPS conditions, both naproxen and licofelone inhibited LXA4, inducing an increase in the LTB4/LXA4 ratio with naproxen treatment but not with licofelone. Under these conditions, naproxen treatment induced a higher level of IL-1beta production. CONCLUSION: We demonstrated in OA synovium that a shunt from AA to the LOX pathway occurred and that treatment with a nonselective COX inhibitor could increase the production of LTB4 and secondarily the synthesis of IL-1beta. Therefore treatment with licofelone, which can act on both COX and LOX pathways, may have some interesting properties in the treatment of OA.

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The Journal of Rheumatology
Vol. 32, Issue 4
1 Apr 2005
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Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.
Patrick Marcouiller, Jean-Pierre Pelletier, Mélanie Guévremont, Johanne Martel-Pelletier, Pierre Ranger, Stefan Laufer, Pascal Reboul
The Journal of Rheumatology Apr 2005, 32 (4) 704-712;

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Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.
Patrick Marcouiller, Jean-Pierre Pelletier, Mélanie Guévremont, Johanne Martel-Pelletier, Pierre Ranger, Stefan Laufer, Pascal Reboul
The Journal of Rheumatology Apr 2005, 32 (4) 704-712;
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