Evaluation of the Bcl-2 family antagonist ABT-737 in collagen-induced arthritis

Kate E. Lawlor, Scott D. Smith, Annemarie van Nieuwenhuijze, David C.S. Huang, Ian P. Wicks

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)819-829
Number of pages11
JournalJournal of leukocyte biology
Volume90
Issue number4
DOIs
Publication statusPublished - 1 Oct 2011
Externally publishedYes

Keywords

  • Apoptosis
  • Autoimmunity
  • Mcl-1
  • Rheumatoid arthritis

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