Background Galectin-3 is a β-galactoside-binding lectin that plays an important role in the modulation of immune responses. Galectin-3 levels are increased in rheumatoid arthritis (RA) synovial tissue, synovial fluid and peripheral blood1. Recombinant exogenous galectin-3 stimulates pro-inflammatory cytokine secretion by fibroblast-like synoviocytes (FLS)2. In a murine, antigen-induced arthritis model, Gal-3-/- mice displayed significantly reduced synovitis and joint erosion compared to WT mice3.
Objectives To examine the effect of galectin-3 inhibition on toll-like receptor (TLR)-induced secretion of interleukin-6 (IL-6) in FLS from RA and osteoarthritis (OA) patients.
Methods FLS from RA and OA patients were harvested from synovial fluid aspirates or directly from synovial tissue obtained during orthopedic surgery. Galectin-3 was inhibited either by siRNA mediated gene-knockdown, or by the galectin ligands thiodigalactoside and modified citrus pectin (MCP). The cells were then stimulated with ligands for TLR-2, 3 and 4; peptidoglycan (PGN), poly(I:C) and lipopolysaccharide (LPS), respectively, and the levels of IL-6 secretion were measured by ELISA.
Results Galectin-3 gene knockdown inhibited TLR-2, 3 and 4 induced IL-6 secretion in FLS. Treatment with thiodigalactoside, a galectin oligosaccharide ligand, also decreased TLR-meditated IL-6 secretion. Treatment with MCP, a polysaccharide galectin-3 ligand, attenuated IL-6 secretion due to stimulation with PGN and poly(I:C), but augmented IL-6 secretion following LPS-stimulation, in a dose dependent manner.
Conclusions Galectin-3 modulates TLR-induced IL-6 secretion in FLS. Knockdown of galectin-3 inhibits PGN, poly(I:C) and LPS-induced IL-6 secretion. Galectin-3 saccharide ligands can also inhibit TLR-induced IL-6 secretion. Understanding the role of galectin-3 in TLR-induced cytokine secretion may add new insights into the pathological mechanisms of autoimmunity and perhaps aid in the design of galectin-3 inhibitors as potential therapeutics.
Ohshima S, Kuchen S, Seemayer CA, et al. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum. 2003; 48(10): 2788-95.
Filer A, Bik M, Parsonage GN, et al. Galectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways. Arthritis Rheum. 2009; 60(6): 1604-14.
Forsman H, Islander U, Andreasson E, et al. Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. Arthritis Rheum. 2011; 63(2): 445-54.
Disclosure of Interest None Declared