Halofuginone inhibits NF-kappaB and p38 MAPK in activated T cells.

Abstract

Halofuginone, a low molecular weight plant alkaloid, inhibits collagen alpha1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graft-versus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-beta (TGF-beta), an important immunomodulator. The present study was undertaken to explore the effects of halofuginone on activated T cells. Peripheral blood T cells were activated by anti-CD3 monoclonal antibodies in the absence and presence of halofuginone and assessed for nuclear factor (NF)-kappaB activity, production of tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma), T cell apoptosis, chemotaxis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). A delayed-type hypersensitivity (DTH) model was applied to investigate the effect of halofuginone on T cells in vivo. Preincubation of activated peripheral blood T cells with 10-40 ng/ml halofuginone resulted in a significant dose-dependent decrease in NF-kappaB activity (80% inhibition following incubation with 40 ng halofuginone, P = 0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-alpha, IFN-gamma, interleukin (IL)-4, IL-13, and TGF-beta (P < 0.005). Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P = 0.0001 and 0.005, respectively). In contrast, T cell chemotaxis was not affected. Halofuginone inhibited DTH response in mice, indicating suppression of T cell-mediated inflammation in vivo. Halofuginone inhibits activated peripheral blood T cell functions and proinflammatory cytokine production through inhibition of NF-kappaB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.

• Authors: M Leiba, L Cahalon, A Shimoni, O Lider, A Zanin-Zhorov, I Hecht, U Sela, I Vlodavsky, A Nagler
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 80 Issue 2 Pg. 399-406 (Aug 2006) ISSN: 0741-5400 [Print] United States
• PMID: 16769768 (Publication Type: Journal Article)

Chemical References

• Cytokines
• NF-kappa B
• Piperidines
• Quinazolines
• Quinazolinones
• p38 Mitogen-Activated Protein Kinases
• halofuginone

Topics

• Apoptosis
• Chemotaxis
• Cytokines (immunology)
• Dose-Response Relationship, Drug
• Humans
• Lymphocyte Activation
• NF-kappa B (metabolism)
• Phosphorylation
• Piperidines
• Quinazolines (pharmacology)
• Quinazolinones
• Signal Transduction
• T-Lymphocytes (metabolism, physiology)
• p38 Mitogen-Activated Protein Kinases (metabolism)