title: Galectin-3 is a sensor-regulator of toll-like receptor pathways in synovial fibroblasts.
abstract: Galectin-3 is a β-galactoside-binding lectin that plays an important role in the modulation of immune responses. It has been shown to aggravate joint inflammation and destruction in experimental arthritis. We investigated the role of galectin-3 in TLR-induced cell activation in human synovial fibroblasts (SF) in order to better understand the mechanism(s) of the proinflammatory function of galectin-3 in arthritis. Galectin-3 expression in SF obtained from rheumatoid arthritis and osteoarthritis patients was inhibited by siRNA mediated gene-knockdown. Galectin-3 was also inhibited with modified citrus pectin (MCP), a polysaccharide galectin-3 ligand. Galectin-3 knockdown inhibited TLR-2, -3 and -4-induced IL-6 secretion, but not TLR-2, -3 and -4-mediated matrix metalloproteinase-3 or CC chemokine ligand-5 secretion. When the SF were stimulated with phorbol 12-myristate 13-acetate, a protein kinase C activator that bypasses the membranal receptors, galectin-3 knockdown no longer influenced IL-6 secretion. MCP reduced IL-6 levels in a dose-dependent manner. Our results indicate that galectin-3 is a positive sensor-regulator of TLR-induced IL-6 secretion in human synovial fibroblasts, thus adding new insights into the mechanisms by which galectin-3 augments synovial inflammation. These findings corroborate the potential role of glycan inhibitors of galectin-3 as a therapeutic approach for the treatment of inflammatory arthritis.
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel. Electronic address: uria@tlvmc.gov.il.
authors.forename: Uri
authors.initials: U
authors.lastname: Arad
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Madar-Balakirski
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Angel-Korman
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Amir
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Tzadok
authors.affiliation: Division of Orthopedics, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Segal
authors.affiliation: Division of Orthopedics, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Menachem
authors.affiliation: Division of Orthopedics, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Aviram
authors.initials: A
authors.lastname: Gold
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Elkayam
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Caspi
mesh_terms: D018946:Chemokine CCL5 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D037502:Galectin 3 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D037502:Galectin 3; D015850:Interleukin-6; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D051193:Toll-Like Receptors; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D013755:Tetradecanoylphorbol Acetate
keywords: Galectin-3; Rheumatoid Arthritis; Synovial fibroblasts; Synovitis; Toll-like receptors