Evaluation of the Bcl-2 family antagonist ABT-737 in collagen-induced arthritis
- Author(s)
- Lawlor, KE; Smith, SD; van Nieuwenhuijze, A; Huang, DCS; Wicks, IP;
- Details
- Publication Year 2011-10,Volume 90,Issue #4,Page 819-829
- Journal Title
- JOURNAL OF LEUKOCYTE BIOLOGY
- Publication Type
- Journal Article
- 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-xL, 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. Naive 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 BclxL, 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. J. Leukoc. Biol. 90: 819-829; 2011.
- Publisher
- FEDERATION AMER SOC EXP BIOL
- Keywords
- COLONY-STIMULATING FACTOR; BH3 MIMETIC ABT-737; T-CELL; INFLAMMATORY ARTHRITIS; RHEUMATOID-ARTHRITIS; IN-VIVO; SYNOVIAL FIBROBLASTS; JOINT INFLAMMATION; INTERFERON-GAMMA; TRANSGENIC MICE
- Publisher's Version
- https://doi.org/10.1189/jlb.0311174
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- Refer to copyright notice on published article.
Creation Date: 2011-10-01 12:00:00