Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis

John C. Scatizzi, Jack Hutcheson, Richard M. Pope, Gary S. Firestein, Alisa E. Koch, Melissa Mavers, Avraham Smason, Hemant Agrawal, G. Kenneth Haines, Navdeep S. Chandel, Richard S. Hotchkiss, Harris Perlman

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Abstract

Objective. Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl-2 homology 3 (BH3) domain-only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease. Methods. Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim-/- mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and immunoblotting. Bim-/- mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum-transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT-BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis. Results. The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim-/- macrophages displayed elevated expression of markers of inflammation and secreted more interleukin-1β following stimulation with LPS or thioglycollate. TAT-BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity. Conclusion. These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA.

Original languageEnglish (US)
Pages (from-to)441-451
Number of pages11
JournalArthritis and rheumatism
Volume62
Issue number2
DOIs
StatePublished - Feb 1 2010

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Scatizzi, J. C., Hutcheson, J., Pope, R. M., Firestein, G. S., Koch, A. E., Mavers, M., Smason, A., Agrawal, H., Haines, G. K., Chandel, N. S., Hotchkiss, R. S., & Perlman, H. (2010). Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis. Arthritis and rheumatism, 62(2), 441-451. https://doi.org/10.1002/art.27198