title: Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis.
abstract: OBJECTIVE
  Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis.
  
  
  METHODS
  Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint.
  
  
  RESULTS
  Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium.
  
  
  CONCLUSIONS
  Local, but not systemic administration of uridine efficiently prevented development of antigen-induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.
authors.affiliation: Autoimmunity & Immune Regulation (AIR), Department of Clinical & Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Chenna Narendra
authors.affiliation: Autoimmunity & Immune Regulation (AIR), Department of Clinical & Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Jaya Prakash
authors.initials: JP
authors.lastname: Chalise
authors.affiliation: Autoimmunity & Immune Regulation (AIR), Department of Clinical & Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Magnusson
authors.affiliation: Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Uppugunduri
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000941:Antigens / Q000276:immunology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018821:CD18 Antigens / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D007270:Injections, Intra-Articular; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D012710:Serum Albumin, Bovine / Q000009:adverse effects / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism; D014529:Uridine / Q000008:administration & dosage*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000941:Antigens; D018821:CD18 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; C029180:methylated bovine serum albumin; D018799:Intercellular Adhesion Molecule-1; D012710:Serum Albumin, Bovine; D014529:Uridine