title: Free fatty acids: potential proinflammatory mediators in rheumatic diseases.
abstract: OBJECTIVE
  Due to their role in inflammatory metabolic diseases, we hypothesised that free fatty acids (FFA) are also involved in inflammatory joint diseases. To test this hypothesis, we analysed the effect of FFA on synovial fibroblasts (SF), human chondrocytes and endothelial cells. We also investigated whether the toll-like receptor 4 (TLR4), which can contribute to driving arthritis, is involved in FFA signalling.
  
  
  METHODS
  Rheumatoid arthritis SF, osteoarthritis SF, psoriatic arthritis SF, human chondrocytes and endothelial cells were stimulated in vitro with different FFA. Immunoassays were used to quantify FFA-induced protein secretion. TLR4 signalling was inhibited extracellularly and intracellularly. Fatty acid translocase (CD36), responsible for transporting long-chain FFA into the cell, was also inhibited.
  
  
  RESULTS
  In rheumatoid arthritis synovial fibroblasts (RASF), FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes pro-MMP1 and MMP3. The intensity of the response was mainly dependent on the patient rather than on the type of disease. Both saturated and unsaturated FFA showed similar effects on RASF, while responses to the different FFA varied for human chondrocytes and endothelial cells. Extracellular and intracellular TLR4 inhibition as well as fatty acid transport inhibition blocked the palmitic acid-induced IL-6 secretion of RASF.
  
  
  CONCLUSIONS
  The data show that FFA are not only metabolic substrates but may also directly contribute to articular inflammation and degradation in inflammatory joint diseases. Moreover, the data suggest that, in RASF, FFA exert their effects via TLR4 and require extracellular and intracellular access to the TLR4 receptor complex.
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Frommer
authors.affiliation: Department of Internal Medicine III, Endocrinology, Diabetes, Metabolism, Justus-Liebig-University of Giessen, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffler
authors.affiliation: Department of Orthopedics and Trauma Surgery, Markus Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rehart
authors.affiliation: Department of Orthopedics and Trauma Surgery, Markus Hospital, Frankfurt, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Lehr
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Müller-Ladner
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Neumann
mesh_terms: D015535:Arthritis, Psoriatic / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000187:drug effects / Q000276:immunology; D019902:Chondrocytes / Q000187:drug effects / Q000276:immunology*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D005230:Fatty Acids, Nonesterified / Q000276:immunology* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000187:drug effects / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000276:immunology; D010003:Osteoarthritis / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013583:Synovial Membrane / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018955:CD36 Antigens; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D005230:Fatty Acids, Nonesterified; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1