TY - JOUR
T1 - Evaluation of the Bcl-2 family antagonist ABT-737 in collagen-induced arthritis
AU - Lawlor, Kate E.
AU - Smith, Scott D.
AU - van Nieuwenhuijze, Annemarie
AU - Huang, David C.S.
AU - Wicks, Ian P.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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 Bclx 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.
AB - 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 Bclx 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.
KW - Apoptosis
KW - Autoimmunity
KW - Mcl-1
KW - Rheumatoid arthritis
UR - http://www.scopus.com/inward/record.url?scp=80053361349&partnerID=8YFLogxK
U2 - 10.1189/jlb.0311174
DO - 10.1189/jlb.0311174
M3 - Article
C2 - 21719460
AN - SCOPUS:80053361349
VL - 90
SP - 819
EP - 829
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
SN - 0741-5400
IS - 4
ER -