Published online before print June 12, 2006

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(Journal of Leukocyte Biology. 2006;80:399-406.)
© 2006 by Society for Leukocyte Biology

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

M. Leiba^*, L. Cahalon, A. Shimoni^*, O. Lider, A. Zanin-Zhorov, I. Hecht, U. Sela, I. Vlodavsky and A. Nagler^*,1

^* The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, and Sackler Medical School, Tel-Aviv University, Israel;
Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel; and
Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel

¹Correspondence: Division of Hematology, BMT and CBB, Chaim Sheba Medical Center, Tel-Hashomer, Israel 52621. E-mail: a.nagler{at}sheba.health.gov.il

Halofuginone, a low molecular weight plant alkaloid, inhibits collagen 1 (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-ß (TGF-ß), 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)-B activity, production of tumor necrosis factor (TNF-) and interferon- (IFN-), 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-B activity (80% inhibition following incubation with 40 ng halofuginone, P=0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-, IFN-, interleukin (IL)-4, IL-13, and TGF-ß (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-B activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.

Key Words: TGF-ß • TNF-

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