1. ¹Department of Immunology, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark
2. ²Department of Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark
3. ³Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
4. ⁴Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: Dr N Ødum, Institute of Medical Microbiology and Immunology, University of Copenhagen, Blegdamsvej 3c, DK-2200 Copenhagen N, Denmark. E-mail: n.odum@immi.ku.dk

Received 21 June 2006; Accepted 29 June 2006; Published online 17 August 2006.

Abstract

Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL.