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

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 1ß (IL-1ß) 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-1ß 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-1ß 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-1ß. 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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https://hal.univ-lorraine.fr/hal-01705121
Contributor : Pascal Reboul <>
Submitted on : Friday, February 9, 2018 - 10:06:54 AM
Last modification on : Monday, July 20, 2020 - 12:33:14 PM

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  • HAL Id : hal-01705121, version 1
  • PUBMED : 15801029

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Patrick Marcouiller, Pierre Pelletier, Mélanie Guévremont, Johanne Martel-Pelletier, Pierre Ranger, et al.. Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.. Journal of Rheumatology, Journal of Rheumatology Publishing Company Limited, 2005, pp.704-12. ⟨hal-01705121⟩

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