Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 90, Issue 4, Pages 819-829Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.0311174
Keywords
Mcl-1; autoimmunity; rheumatoid arthritis; apoptosis
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Funding
- Reid Charitable Trust (Australia)
- NHMRC [356267, 461203, 516701, 461221]
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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.
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