title: Increased lymphocyte apoptosis in mouse models of colitis upon ABT-737 treatment is dependent upon BIM expression.
abstract: Exaggerated activation of lymphocytes contributes to the pathogenesis of inflammatory bowel disease (IBD). Medical therapies are linked to the BCL-2 family-mediated apoptosis. Imbalance in BCL-2 family proteins may cause failure in therapeutic responses. We investigated the role of BCL-2 inhibitor ABT-737 for lymphocyte apoptosis in mice under inflammatory conditions. B.6129P2-interleukin (IL)-10(tm1Cgn) /J (IL-10(-/-) ) weighing 25-30 g with ongoing colitis were used. Fifty mg/kg/day ABT-737 was injected intraperitoneally (i.p.). Haematological analyses were performed with an ADVIA 2120 flow cytometer and mass cytometry with a CyTOF 2. Following i.p. administration, ABT-737 was detected in both spontaneous and acute colitis in peripheral blood (PBL) and colon tissue. Treatment led to lymphopenia. CD4(+) CD44(+) CD62L(+) central memory and CD8(+) , CD44(+) CD62L(-) central memory T cells were decreased in PBL upon ABT-737 compared to vehicle-receiving controls. Increased apoptosis upon ABT-737 was determined in blood lymphocytes, splenocytes and Peyer's patches and was accompanied by a decrease in TNF and IL-1B. ABT-737 positively altered the colonic mucosa and ameliorated inflammation, as shown by colonoscopy, histology and colon length. A decreased BIM/BCL-2 ratio or absence of BIM in both Bim(-) (/) (-) and Il10(-) (/) (-) × Bim(-) (/) (-) impeded the protective effect of ABT-737. The BIM/BCL-2 ratio decreased with age and during the course of treatment. Thus, long-term treatment resulted in adapted TNF levels and macroscopic mucosal damage. ABT-737 was efficacious in diminishing lymphocytes and ameliorating colitis in a BIM-dependent manner. Regulation of inappropriate survival of lymphocytes by ABT-737 may provide a therapeutic strategy in IBD.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich.
authors.forename: C
authors.initials: C
authors.lastname: Lutz
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich.
authors.forename: M
authors.initials: M
authors.lastname: Mozaffari
authors.affiliation: Flow Cytometry Facility, University Zürich.
authors.forename: V
authors.initials: V
authors.lastname: Tosevski
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich.
authors.forename: M
authors.initials: M
authors.lastname: Caj
authors.affiliation: Division of Nephrology, University Hospital Zurich, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Cippà
authors.affiliation: AbbVie Bioresearch Center, AbbVie Worcester, MA, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: McRae
authors.affiliation: AbbVie Bioresearch Center, AbbVie Worcester, MA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Graff
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich.
authors.forename: G
authors.initials: G
authors.lastname: Rogler
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich.
authors.forename: M
authors.initials: M
authors.lastname: Fried
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich.
authors.forename: M
authors.initials: M
authors.lastname: Hausmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D015870:Gene Expression; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D008231:Lymphopenia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001713:Biphenyl Compounds; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C556062:IL10 protein, mouse; D053583:Interleukin-1beta; D008565:Membrane Proteins; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C052617:Bcl2 protein, mouse; D019041:L-Selectin; D016753:Interleukin-10; D016264:Dextran Sulfate
keywords: ABT-737; BCL-2; BIM; IBD; apoptosis; mucosal T cell turnover
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