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.