Halofuginone inhibits NF-κB and p38 MAPK in activated T cells

M. Leiba, L. Cahalon, A. Shimoni, O. Lider, A. Zanin-Zhorov, I. Hecht, U. Sela, I. Vlodavsky, A. Nagler

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39 Scopus citations

Abstract

Halofuginone, a low molecular weight plant alkaloid, inhibits collagen α1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graftversus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-β (TGF-β), 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)-κB activity, production of tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ), 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-κB activity (80% inhibition following incubation with 40 ng halofuginone, P=0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-α, IFN-γ, interleukin (IL)-4, IL-13, and TGF-β (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-κB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.

Original languageEnglish
Pages (from-to)399-406
Number of pages8
JournalJournal of Leukocyte Biology
Volume80
Issue number2
DOIs
StatePublished - 1 Aug 2006
Externally publishedYes

Keywords

  • TGF-β
  • TNF-α

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