title: Gene expression of catalytic proteasome subunits and resistance toward proteasome inhibition of B lymphocytes from patients with primary sjogren syndrome.
abstract: OBJECTIVE
  Dysregulation of proteasome subunit β1i expression has been shown in total blood mononuclear cells (PBMC) from patients with primary Sjögren syndrome (pSS), a B cell-driven systemic autoimmune disorder.
  
  
  METHODS
  Proteasome activation was investigated in sorted blood cells from patients with pSS and controls by measuring transcript levels of constitutive (β1/β2/β5) and corresponding immunoproteasome catalytic subunits (β1i/β2i/β5i) using real-time PCR. At protein level, β1i protein expression was analyzed by immunoblotting. Functional effects of proteasome inhibition on proteolytic activity and induction of apoptosis were also evaluated in cellular subsets.
  
  
  RESULTS
  The proteasome was found to be activated in pSS, with upregulation of gene expression of catalytic proteasome subunits. Western blot analysis revealed decreased β1i protein expression in pSS B lymphocytes, with decreased protein despite increased messenger RNA (mRNA) levels. After proteasome inhibition in vitro, proteolytic activity was less reduced and resistance to apoptosis was increased in B lymphocytes compared to other cells.
  
  
  CONCLUSIONS
  In pSS, catalytic subunits of the proteasome are upregulated at the mRNA level, while dysregulation of subunit β1i is attributed to B lymphocytes. B cell resistance after proteasome inhibition differs from the classical concept of increased susceptibility toward inhibition in activated cells, supporting the novel notion that susceptibility depends on cellular intrinsic factors and on proteasome activation.
authors.affiliation: Rheumatology Research Laboratory, Department of Rheumatology and Clinical Immunology, Charite Universitätsmedizin Berlin, Germany. lorena.martinez_g@charite.de
authors.forename: Lorena
authors.initials: L
authors.lastname: Martinez-Gamboa
authors.forename: Karsten
authors.initials: K
authors.lastname: Lesemann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kuckelkorn
authors.forename: Sonja
authors.initials: S
authors.lastname: Scheffler
authors.forename: Khetam
authors.initials: K
authors.lastname: Ghannam
authors.forename: Martin
authors.initials: M
authors.lastname: Hahne
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber-Elsner
authors.forename: Karl
authors.initials: K
authors.lastname: Egerer
authors.forename: Lydia
authors.initials: L
authors.lastname: Naumann
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.forename: Denise L
authors.initials: DL
authors.lastname: Faustman
authors.forename: Eugen
authors.initials: E
authors.lastname: Feist
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics*; D061988:Proteasome Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012859:Sjogren's Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib; C577981:PSMB1 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: B LYMPHOCYTES; PROTEASOME INHIBITION; PROTEASOME SYSTEM; SJÖGREN SYNDROME