title: IL-10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome.
abstract: BACKGROUND
  Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder of T cell homeostasis caused by mutations that impair FAS-mediated apoptosis. A defining characteristic of ALPS is the expansion of double negative T cells (DNTC). Relatively little is known about how defective FAS-driven cell death and the Bcl-2 apoptotic pathway intersect in ALPS patients.
  
  
  OBJECTIVE
  We studied changes in Bcl-2 family member expression in ALPS to determine whether the Bcl-2 pathway might provide a therapeutic target.
  
  
  METHODS
  We used flow cytometry to analyze the expression of pro- and anti-apoptotic Bcl-2 family members in T cells from 12 ALPS patients and determined the in vitro sensitivity of ALPS DNTC to the pro-apoptotic BH3 mimetic, ABT-737.
  
  
  RESULTS
  The pro-apoptotic molecule, Bim, was significantly elevated in DNTC. Although no general pattern of individual anti-apoptotic Bcl-2 family members emerged, increased expression of Bim was always accompanied by increased expression of at least 1 anti-apoptotic Bcl-2 family member. Strikingly, Bim levels in DNTC correlated significantly with serum IL-10 in ALPS patients, and IL-10 was sufficient to mildly induce Bim in normal and ALPS T cells via a Janus kinase/signal transducer and activator of transcription 3-dependent mechanism. Finally, ABT-737 preferentially killed ALPS DNTC in vitro.
  
  
  CONCLUSIONS
  Combined, these data show that an IL-10/Janus kinase/signal transducer and activator of transcription 3 pathway drives Bim expression in ALPS DNTC, which renders them sensitive to BH3 mimetics, uncovering a potentially novel therapeutic approach to ALPS.
authors.affiliation: Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Omar
authors.initials: O
authors.lastname: Niss
authors.affiliation: Division of Cellular and Molecular Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Allyson
authors.initials: A
authors.lastname: Sholl
authors.affiliation: Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Bleesing
authors.affiliation: Division of Cellular and Molecular Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. Electronic address: david.hildeman@cchmc.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000276:immunology; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D053613:Janus Kinase 1 / Q000235:genetics* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000276:immunology; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; C491901:FAS protein, human; C508609:IL10 protein, human; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D051020:bcl-X Protein; D019014:fas Receptor; D016753:Interleukin-10; D053613:Janus Kinase 1
keywords: ABT-737; ALPS; BH3 mimetic; Bcl-2 pathway; Bim; IL-10; T cell homeostasis; apoptosis; double negative T cells