title: Evaluation of the Bcl-2 family antagonist ABT-737 in collagen-induced arthritis.
abstract: Therapeutic manipulation of cellular apoptosis holds great promise for malignant and potentially nonmalignant diseases. A relative resistance to apoptosis in RA synovium is associated with increased expression of prosurvival Bcl-2 family members. In this study, we demonstrate that treatment of DBA/1 mice, prior to the onset of CIA with ABT-737, a BH3 mimetic targeting Bcl-2, Bcl-w, and Bcl-x(L), ameliorated disease development. In contrast, treatment of mice with ABT-737 in established CIA did not alter the course of disease. ABT-737 induced lymphopenia, however pathogenic lymphoid populations in CIA mice were less affected, as shown by relatively normal T and B cell responses to CII. Naïve lymphocytes were highly sensitive to apoptosis after culture with ABT-737, but synovial macrophages and neutrophils were not. Mcl-1 was detected in synovial monocyte/macrophages and neutrophils and strikingly, its expression, rather than Bcl-2 and Bcl-x(L), increased in the affected paws and lymphoid organs of mice with CIA. These observations implicate Mcl-1, which is not targeted by ABT-737, in the survival of inflammatory cells in established CIA and suggest that antagonism of Mcl-1 may be more effective in diseases such as RA.
authors: Reid Rheumatology Laboratory, Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors: Kate E
authors: KE
authors: Lawlor
authors: Scott D
authors: SD
authors: Smith
authors: Annemarie
authors: A
authors: van Nieuwenhuijze
authors: David C S
authors: DC
authors: Huang
authors: Ian P
authors: IP
authors: Wicks
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; C101155:Bcl2l2 protein, mouse; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein