Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E-2 production in explants of human osteoarthritic knee menisci

Objective. In osteoarthritis (OA), a combination of biochemical and biomech anical factors may damage both menisci and articular cartilage. Nitric oxid e (NO) and prostaglandin E-2 (PGE(2)) have been implicated as mediators of inflammation in OA. The goals of this study were to determine if menisci fr om patients with OA produce NO and PGE(2), and if the proinflammatory cytok ines interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha ), and IL-17 augment NO and PGE(2) production by these tissues. Methods. Menisci were obtained from 17 patients (age 47-75 years) undergoin g total knee replacement for OA. Tissue explants were cultured alone or wit h IL-1 beta, IL-17, or TNF alpha, and the release of NO and PGE(2) from the tissue as well as the presence of type 2 nitric oxide synthase (NOS2) and cyclooxygenase 2 (COX-2) antigens were measured. Results. All menisci constitutively produced NO, and significant increases in NO production were observed in the presence of IL-1 beta, TNF alpha, or IL-17 (P < 0.05). The combination of IL-17 and TNF<alpha> significantly inc reased NO production compared with either cytokine alone. Basal and cytokin e-stimulated NO synthesis was inhibited by the NOS inhibitors N-G-monomethy l-L-arginine or N-3-aminoethylbenzylacetamidine (1400W). IL-10 significantl y increased PGE(2) production. The combination of IL-10 and TNF alpha had a n additive effect on PGE(2) production, while addition of IL-17 to TNF alph a or IL-1 beta synergistically enhanced PGE(2) production. Inhibition of NO production by 1400W significantly increased IL-1 beta -stimulated PGE(2) p roduction, and inhibition of PGE(2) production by the COX-2 inhibitor N-[2- (cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide significantly increased I L-17-stimulated NO production. Conclusion. Menisci from humans with OA spontaneously produced NO and PGE(2 ) in a manner that was synergistically or additively augmented by cytokines . NO and PGE(2) exhibited reciprocal regulatory effects on one another, sug gesting that pharmaceutical agents designed to inhibit NOS2 or COX-2 produc tion may in fact be influencing both pathways.