title: Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl-2 homology 3 (BH3) domain-only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease.
  
  
  METHODS
  Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim(-/-) mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and immunoblotting. Bim(-/-) mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum-transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT-BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis.
  
  
  RESULTS
  The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim(-/-) macrophages displayed elevated expression of markers of inflammation and secreted more interleukin-1beta following stimulation with LPS or thioglycollate. TAT-BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity.
  
  
  CONCLUSIONS
  These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA.
authors.affiliation: St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Scatizzi
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
authors.forename: Melissa
authors.initials: M
authors.lastname: Mavers
authors.forename: Avraham
authors.initials: A
authors.lastname: Smason
authors.forename: Hemant
authors.initials: H
authors.lastname: Agrawal
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D009504:Neutrophils / Q000473:pathology; D010003:Osteoarthritis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D013585:Synovitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2