Mechanism of action of polyunsaturated fatty acids in rheumatoid arthritis.

There is now considerable evidence that inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor play a major role in chronic inflammatory diseases such as rheumatoid arthritis (RA) [ 11, the main site of which is the synovial lining of joints. Within the synovium, cells such as macrophages, fibroblasts and endothelial cells are capable of producing 1L-1 and TNF [ l ] and it is therefore likely that these cytokines are involved in the initiation and prolongation of the inflammation of the synovium as well as directly causing cartilage erosion. RA is presently treated by a wide range of drugs, principally non-steroidal anti-inflammatory drugs or disease-modifying drugs (second line drugs), but a novel approach to the treatment of the disease has been suggested by several limited studies involving treatment of patients with polyunsaturated fatty acids [2]. These compounds appear to be beneficial in the treatment of disease and their effects could be due to a number of mechanisms including reduced production of pro-inflammatory cytokines, changes in cell membrane lipids altering transduction pathways and/or manipulation of eicosanoid products [3,4]. In the present studies, monocyte cells were cultured with or without stimulation in the presence or absence of polyunsaturated fatty acids and both cellular proliferation and IL-1 secretion were measured. U937 cells are a monocytic tumour cell line which may serve as a model for human monocytes. The cells were grown at a density of 2 x lo4 cells/ml in 96-well microtitre plates (200 pl/well) in RPMl 1640 medium containing glutamine (2 mM), penicillin/streptomycin ( 100 i.u./ml) and foetal calf serum (v/v. 5%). The plates were incubated for 24 h at 37°C in a humidified incubator (5% CO,/air) after which aliquots (4 p l ) of a solution ( 2 mg of oil/ml) containing either fish oil (1 9% fatty acid as eicosapentaenoic acid plus 12% as docosahexaenoic acid), evening primrose oil (8% fatty acid as y-linoleic acid plus 70*/, as linoleic acid) or olive oil control (80% fatty acid as oleic acid plus 8"/0 as linoleic acid) were added to appropriate wells. After a further 24 h incubation period under the same conditions, [3H]thymidine (0.5 pCi) was added to each well and the incubation continued for a further 4 h. Cells were harvested on to glass fibre