title: A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis.
abstract: OBJECTIVE
  Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.
  
  
  METHODS
  Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.
  
  
  RESULTS
  RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.
  
  
  CONCLUSIONS
  ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.
authors.affiliation: Department of Biomedicine.
authors.forename: Morten Aagaard
authors.initials: MA
authors.lastname: Nielsen
authors.affiliation: Department of Biomedicine.
authors.forename: Thomas
authors.initials: T
authors.lastname: Andersen
authors.affiliation: Department of Biomedicine.
authors.forename: Anders
authors.initials: A
authors.lastname: Etzerodt
authors.affiliation: Department of Biomedicine.
authors.forename: Tue Wenzel
authors.initials: TW
authors.lastname: Kragstrup
authors.affiliation: Department of Biomedicine, Department of Rheumatology.
authors.forename: Tue Kruse
authors.initials: TK
authors.lastname: Rasmussen
authors.affiliation: Department of Rheumatology. Department of Clinical Medicine, Aarhus University, Aarhus.
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.affiliation: Department of Rheumatology, Copenhagen University Hospital Glostrup, Glostrup, Denmark Center for Rheumatology and Spine Diseases, Glostrup Hospital.
authors.forename: Merete Lund
authors.initials: ML
authors.lastname: Hetland
authors.affiliation: Department of Rheumatology, King Christian 10th Hospital for the Rheumatic Diseases, Denmark Institute of Health Research, University of Southern Denmark, Gråsten, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.affiliation: Department of Rheumatology, University of Southern Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Junker
authors.affiliation: Department of Rheumatology, Copenhagen University Hospital Glostrup, Glostrup, Denmark Center for Rheumatology and Spine Diseases, Glostrup Hospital.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Østergaard
authors.affiliation: Department of Biomedicine, Department of Clinical Medicine, Aarhus University, Aarhus.
authors.forename: Malene
authors.initials: M
authors.lastname: Hvid
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital and Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
authors.affiliation: Department of Biomedicine, Department of Rheumatology. Department of Clinical Medicine, Aarhus University, Aarhus, bd@biomed.au.dk.
authors.forename: Bent
authors.initials: B
authors.lastname: Deleuran
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism / Q000502:physiology*; D000072198:ADAM17 Protein / Q000502:physiology*; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D018450:Disease Progression; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D037161:Galectins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear; D008137:Longitudinal Studies; D053515:Matrix Metalloproteinase 17 / Q000502:physiology*; D008727:Methotrexate / Q000627:therapeutic use; D013582:Synovial Fluid / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053330:4-1BB Ligand; D018501:Antirheumatic Agents; D001323:Autoantibodies; D037161:Galectins; C105032:LGALS9 protein, human; D014409:Tumor Necrosis Factor-alpha; D053515:Matrix Metalloproteinase 17; D000072198:ADAM17 Protein; D008727:Methotrexate
keywords: 4-1BB; 4-1BBL; ADAM17; DAS28; TACE; TNF; galectin; outcome; rheumatoid arthritis; synovium