Suppression of human synovial cell proliferation by dihomo‐γ‐linolenic acid

Abstract

Prostaglandin E1 (PGE1) and oils enriched in its precursor fatty acids suppress inflammation and joint tissue injury in several animal models. Since synovial cell proliferation is a hallmark of rheumatoid arthritis, we studied the effect of dihomo‐γ‐linolenic acid (DGLA), an immediate precursor of PGE1, on the growth of human adherent synovial cells (ASC) in tissue culture. When stimulated by appropriate concentrations of recombinant interleukin‐1β (rIL‐1β), ASC proliferate and produce PGE. DGLA‐enriched medium suppressed both baseline and rIL‐1β–stimulated ASC growth fivefold, compared with medium supplemented with arachidonic acid. Indomethacin reduced the effect of the DGLA. Synovial cells incorporated the DGLA, and rIL‐1β–stimulated cells that were incubated with DGLA exhibited a 14‐fold increase in PGE1 (to 25.2 ± 6.0 ng/ml, mean ± SD) and a 70% decrease in PGE2 (to 25.2 ± 4.2 ng/ml) compared with cells in control medium. At equivalent concentrations (5 × 10−7M), PGE1 increased the level of cellular cAMP to a greater extent than did PGE2 (16.8 ± 2.0 pmoles versus 4.3 ± 1.9 pmoles, mean ± SEM). Exogenous PGE1 was also a more effective inhibitor of cell growth. Similarly, cAMP concentrations in cells exposed to DGLA for 6 hours were greater than concentrations in arachidonic acidenriched cultures (17.8 ± 3.3 pmoles versus 2.1 ± 2.0 pmoles). These observations suggest that DGLA can restrain ASC growth, an effect which may be due to its capacity to increase PGE1 production and subsequent cellular cAMP concentration.

Gammalinolenic Acid, an Unsaturated Fatty Acid with Anti-Inflammatory Properties, Blocks Amplification of IL-1β Production by Human Monocytes

“…Although it appears that the major mechanism whereby GLA reduces secretion of IL-1␤ from LPS-stimulated cells is by reduction of autoinduction, an effect on secretion itself is not excluded by our studies. Increases in cellular concentrations of cAMP result in reduced secretion of lysosomal products from activated human neutrophils (36), and DGLA increases cAMP in human synovial cells (2). Thus, the ability of GLA to alter IL-1␤ secretion directly needs to be addressed.…”

“…It is metabolized to dihomogammalinolenic acid (DGLA; 20:3n6), the immediate precursor of PGE 1 , an eicosanoid with known antiinflammatory and immunoregulatory properties (1)(2)(3)(4). GLA and DGLA also modulate immune responses in an eicosanoid-independent manner by acting directly on T lymphocytes (5-7).…”

Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma‐linolenic acid

“…Perhaps measurement of PGE, production by larger numbers of cells will be necessary. Increases in PGE, production by platelets were seen after ingestion of DGLA by human volunteers (1 l), and addition of DGLA to human synovial cells in vitro leads to a marked reduction in PGE, synthesis and a substantial increase in PGE, production by these cells (25). PGE, and PGE, do have different biologic activities.…”

Gammalinolenic acid treatment of rheumatoid arthritis

“…Thus, the observation [27] that DGLA and docosahexaenoic acid (DHA; 22:6n-3, a major component of fish oil) selectively increase steady state mRNA levels of plasminogen activator inhibitor-l in human endothelial cells in culture may be potentially important. Addition of DGLA to human synovial cells in culture reduces PGE 2 , increases PGE 1 , and restrains IL-l stimulated synovial cell growth [13]. The antiproliferative effect of DGLA is prevented in large part by indomethacin addition to cells.…”

“…PGE1 suppresses diverse effector systems of inflammation and reduces acute and chronic inflammation in several animal models [12]. In addition, PGE1 suppresses synovial cell growth [13]. Also, non-steroidal anti-inflammatory drug (NSAID) induced downregulation of the glucocorticoid receptor in human synovial fibroblasts, which limits the ability of corticosteroids to suppress metalloproteinase production, is prevented by a PGE 1 analog [14].…”