Leukotriene and Prostaglandin Synthesis Pathways in Osteoarthritic Synovial Membranes: Regulating Factors for Interleukin 1ß Synthesis

PATRICK MARCOUILLER, JEAN-PIERRE PELLETIER, MÉLANIE GUÉVREMONT, JOHANNE MARTEL-PELLETIER, PIERRE RANGER, STEFAN LAUFER, and PASCAL REBOUL

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. (J Rheumatol 2005;32:704-12)

Key Indexing Terms:

LEUKOTRIENES
PROSTAGLANDINS
SYNOVIAL MEMBRANES
OSTEOARTHRITIS
INTERLEUKIN 1

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From the Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre hospitalier de l'Université de Montréal, Montréal, Québec; Department of Orthopaedics, Hôpital Sacré-Coeur, Montréal, Québec; and Eberhard-Karls University, Tübingen, Germany.

Supported in part by a grant from Merckle GmbH, Ulm, Germany, and by la Chaire en Arthrose, Université de Montréal. P. Marcouiller is a recipient of the Fonds Marthe-Demers en gérontologie-gériatrie from the University of Montreal. Dr. Reboul is a recipient of the Dr. André Lanthier Scholarship from the University of Montreal.

P. Marcouiller, MSc; J-P. Pelletier, MD; M. Guévremont, MSc; J. Martel-Pelletier, PhD; P. Reboul, PhD, Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre hospitalier de l'Université de Montréal; P. Ranger, MD, Department of Orthopaedics, Hôpital Sacré-Coeur; S. Laufer, PhD, Eberhard-Karls University.

Address reprint requests to Dr. P. Reboul, Unité de recherche en arthrose, CR-CHUM Centre hospitalier de l'Université de Montréal, 1560 rue Sherbrooke Est, Pavillon de Sève, Y-2604, Montréal, Québec H2L 4M1. E-mail: pascal.reboul@umontreal.ca

Submitted March 8, 2004; revision accepted November 10, 2004.

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