Abstract
Different members of the galectin family may have inhibitory or stimulatory roles in controlling immune responses and regulating inflammatory reactions in autoimmune diseases such as rheumatoid arthritis (RA). A hypothetical model of a cross talk between galectin-1 and galectin-3 has been established in the circumstance of rheumatoid joints. As galectin-3 is a positive regulator and galectin-1 is a negative regulator of inflammation and autoimmune responses, in this study we evaluated the effects of local knockdown of galectin-3 or overexpression of galectin-1 on ameliorating collagen-induced arthritis (CIA) in rats. Lentiviral vectors encoding galectin-3 small hairpin RNA (shRNA) and galectin-1, as well as two control vectors expressing luciferase shRNA and green fluorescent protein, were individually injected intra-articularly into the ankle joints of rats with CIA, and their treatment responses were monitored by measuring the clinical, radiological and histological changes. Our results show that both knockdown of galectin-3 and overexpression of galectin-1 induced higher percentages of antigen-induced T-cell death in the lymph node cells from arthritic rats. Furthermore, these treatments significantly reduced articular index scores, radiographic scores and histological scores, accompanied with decreased T-cell infiltrates and reduced microvessel density in the ankle joints. Our findings implicate galectin-3 and galectin-1 as potential therapeutic targets for the treatment of RA.
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References
Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P . New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370: 1861–1874.
Chang DM . Rheumatoid arthritis. In: Liu HW (ed). Taiwan Rheumatology Textbook. Rheumatology Society of ROC: Taipei, 2003 pp 175–188.
Firestein GS . Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.
Strand V, Kimberly R, Isaacs JD . Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev Drug Discov 2007; 6: 75–92.
Trentham DE, Townes AS, Kang AH . Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 1977; 146: 857–868.
Jou IM, Shiau AL, Chen SY, Wang CR, Shieh DB, Tsai CS et al. Thrombospondin 1 as an effective gene therapeutic strategy in collagen-induced arthritis. Arthritis Rheum 2005; 52: 339–344.
Wang CR, Chen SY, Wu CL, Liu MF, Jin YT, Chao L et al. Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation. Arthritis Rheum 2005; 52: 1319–1324.
Shiau AL, Chen SY, Chang MY, Su CH, Chung SY, Yo YT et al. Prothymosin α lacking the nuclear localization signal as an effective gene therapeutic strategy in collagen-induced arthritis. J Immunol 2007; 178: 4688–4694.
Wang CR, Shiau AL, Chen SY, Lin LL, Tai MH, Shieh GS et al. Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer. Arthritis Rheum 2008; 58: 1650–1656.
Rabinovich GA, Toscano MA . Turning ‘sweet’ on immunity: galectin–glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 2009; 9: 338–352.
Ohshima S, Kuchen S, Seemayer CA, Kyburz D, Hirtm A, Klinzing S et al. Galectin-3 and its binding protein in rheumatoid arthritis. Arthritis Rheum 2003; 48: 2788–2795.
Harjacek M, Diaz-Cano S, Miguel MD, Wolfe H, Maldonado CA, Rabinovich GA . Expression of galectin-1 and -3 correlates with defective mononuclear cell apoptosis in patients with juvenile idiopathic arthritis. J Rheumatol 2001; 28: 1914–1922.
Neidhart M, Zaucke F, von Knoch R, Jungel A, Michel BA, Gay RE et al. Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric. Ann Rheum Dis 2005; 64: 419–424.
Rubinstein N, IIarregui JM, Toscano MA, Rabinovich GA . The role of galectin in the initiation, amplification and resolution of the inflammatory response. Tissue Antigens 2004; 64: 1–12.
IIarregui JM, Bianco GA, Toscano MA, Rabinovich GA . The coming of age of galectins as immunomodulatory agents: impact of these carbohydrate binding proteins in T cell physiology and chronic inflammatory disorders. Ann Rheum Dis 2005; 64: 96–103.
Stowell SR, Qian Y, Karmakar S, Koyama NS, Dias-Baruffi M, Leffler H et al. Differential roles of galectin-1 and galectin-3 in regulating leukocyte viability and cytokine secretion. J Immunol 2008; 180: 3091–4102.
Filer A, Bik M, Parsonage GN, Fitton J, Trebilcock E, Howlett K 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: 1604–1614.
Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J et al. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J Exp Med 1999; 190: 385–397.
Shou J, Bull CM, Li L, Qian HR, Wei T, Luo S et al. Identification of blood biomarkers of the rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model. Arthritis Res Ther 2006; 8: R28.
Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E et al. Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor α antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann Rheum Dis 2009; 68: 1247–1254.
Gouze E, Pawliuk R, Pilapil C, Gouze JN, Fleet C, Palmer GD et al. In vivo gene delivery to synovium by lentiviral vectors. Mol Ther 2002; 5: 397–404.
Delgado M, Toscano MG, Benabdellah K, Cobo M, O'Valle F, Gonzalez-Rey E et al. In vivo delivery of lentiviral vectors expressing vasoactive intestinal peptide complementary DNA as gene therapy for collagen-induced arthritis. Arthritis Rheum 2008; 58: 1026–1037.
Liu FT, Rabinovich GA . Galectins as modulators of tumour progression. Nat Rev Cancer 2005; 5: 29–41.
Dumic J, Dabelic S, Flogel M . Galectin-3: an open ended story. Biochim Biophys Acta 2006; 1760: 616–635.
Liu FT, Patterson RJ, Wang JL . Intracellular functions of galectins. Biochim Biophys Acta 2002; 1572: 263–273.
Hsu DK, Yang RY, Liu FT . Galectins in apoptosis. Methods Enzymol 2006; 417: 256–273.
Matarrese P, Tinari N, Semeraro MI, Natoli C, Iacobelli S, Malorni W . Galectin-3 overexpression protects from cell damage and death by influencing mitochondria homeostasis. FEBS Lett 2000; 473: 311–315.
Hsu DK, Hammes SR, Kuwabara I, Greene WC, Liu FT . Human T lymphotropic virus-1 infection of human T lymphocytes induces expression of the β-galactose-binding lectin, galectin-3. Am J Pathol 1996; 148: 1661–1670.
Sano H, Hsu DK, Apgar JR, Yu L, Sharma BB, Kuwabara I et al. Critical role of galectin-3 in phagocytosis by macrophages. J Clin Invest 2003; 112: 389–397.
Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A, Spitz L et al. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 1993; 365: 666–669.
Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272: 263–267.
Lewis PF, Emerman M . Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J Virol 1994; 68: 510–516.
Gouze E, Pawliuk R, Gouzw JN, Pilapil C, Fleet C, Palmer GD et al. Lentiviral-mediated gene delivery to synovium: potent intra-articular expression with amplification by inflammation. Mol Ther 2003; 7: 460–466.
Gouze E, Gouze JN, Palmer GD, Pilapil C, Evans CH, Ghivizzani SC . Transgene persistence and cell turnover in the diarthrodial joint: implications for gene therapy of chronic joint diseases. Mol Ther 2007; 15: 1114–1120.
Yang RY, Rabinovich GA, Liu FT . Galectins: structure, function and therapeutic potential. Expert Rev Mol Med 2008; 10: e17.
Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ et al. Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol 2000; 156: 899–909.
Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S et al. Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci USA 2006; 103: 15975–15980.
Nangia-Makker P, Raz T, Tait L, Hogan V, Fridman R, Raz A . Galectin-3 cleavage: a novel surrogate marker for matrix metalloproteinase activity in growing breast cancers. Cancer Res 2007; 67: 11760–11768.
Mor F, Quintana FJ, Cohen IR . Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol 2004; 172: 4618–4623.
Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 2008; 27: 3746–3753.
Salmon P, Trono D . Production and titration of lentiviral vectors. In: Current Protocols in Human Genetics. John Wiley & Sons: New York, 2007 Unit 12.10.1-12.10.24.
Morgan K, Clague RB, Shaw MJ, Holt PJ . Native type II collagen-induced arthritis in the rat. I. Incidence and humoral response to collagen. Ann Rheum Dis 1980; 39: 285–290.
Tsai CY, Shiau AL, Chen SY, Chen YH, Cheng PC, Chang MY et al. Amelioration of collagen-induced arthritis in rats by nanogold. Arthritis Rheum 2007; 56: 544–554.
Woods JM, Katschke KJ, Volin MV, Ruth JH, Woodruff DC, Amin MA et al. IL-4 adenoviral gene therapy reduces inflammation, proinflammatory cytokines, vascularization, and bony destruction in rat adjuvant-induced arthritis. J Immunol 2001; 166: 1214–1222.
Acknowledgements
We thank Dr D Trono (Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland) for generously providing pWPT, pWPXL, pLVTHM, psPAX2 and pMD2G plasmids for lentivirus production. We also thank Dr LJ Chang (Department of Molecular Genetics and Microbiology, University of Florida) for providing TE671 cells. This work was supported by grants from the Department of Health, Executive Yuan (DOH96-TD-I-111-TM014 and DOH97-TD-I-111-TM015), National Science Council (NSC96-2314-B-006-002 and NSC98-2628-B-006-014-MY3), and National Cheng Kung University Landmark Project (NCKU-97-R10), Taiwan.
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Wang, CR., Shiau, AL., Chen, SY. et al. Intra-articular lentivirus-mediated delivery of galectin-3 shRNA and galectin-1 gene ameliorates collagen-induced arthritis. Gene Ther 17, 1225–1233 (2010). https://doi.org/10.1038/gt.2010.78
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DOI: https://doi.org/10.1038/gt.2010.78
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