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Introduction: The mono- and digalactosyldiacylglycerol (MGDG and DGDG) galactolipids have been purified from the thermophilic blue-green alga Phormidium sp. ETS-05 that colonizes the therapeutic thermal mud of Abano Terme and Montegrotto Terme, Italy. Both compounds present a marked composition in polyunsaturated fatty acids, mainly omega-3. The therapeutic thermal mud is applied mainly to osteoarthritic cartilage patients. In the present study the effect of MGDG treatment on proteins and factors expressed by human articular cartilage cells in culture and on pathways activated in inflammatory conditions was studied., Methods: Primary cultures of human articular chondrocytes were used at cell passage number 1 (P1). Cells were treated in serum-free medium with inflammatory cytokines in the presence and in the absence of MGDG. Western blot was performed on collected medium and on cell layers. At least three different experiments were performed on primary cultures. The quantitation of the MGDG effect was performed by densitometric scanning of Western blots. p38 Mitogen Activated Protein Kinase (p38) activation, Nuclear Factor-kappaB (NF-kB) activation and Prostaglandin E(2) (PGE(2)) quantitation were performed by commercially available assays. Results are given as the mean values ± SD. All statistical analyses were performed using GraphPad software. The two-tailed Student's t -test was performed., Results: We report that MGDG: 1) represses the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8) induced by interleukin-1alpha (IL-1α) or IL-1α + tumor necrosis factor α (TNFα) interfering with the p38 and NF-kB pathways; 2) is not toxic for the cells and does not affect the cell phenotype; 3) strongly enhances COX-2 expression induced by IL-1α or IL-1α + TNFα; 4) represses mPGES expression induced by IL-1α and the synthesis of PGE(2) and induces the synthesis of 15-deoxy-Δ 12,14-prostaglandin J(2) (15ΔPGJ(2)). In addition, the COX-2 product 15ΔPGJ(2) added to the cells: 1) strongly represses IL-6 and IL-8 induced by IL-1α; 2) represses mPGES expression induced by IL-1α and the synthesis of PGE(2)., Conclusions: All together these data suggest that MGDG has an anti-inflammatory activity in human articular cartilage and possibly activates an anti-inflammatory loop triggered by COX-2 via 15ΔPGJ(2) production, indicating a possible role of COX-2 in resolution of inflammation. The purified compound is a novel anti-inflammatory agent potentially active for human articular cartilage pathologies related to inflammation.