Survivin, a unique member of the inhibitor of apoptosis protein family, is overexpressed in many cancers and considered to play an important role in oncogenesis. We previously reported the survivin expression profile in ATL, a CD4-positive T-cell malignancy caused by HTLV-I. HTLV-I Tax is thought to play an important role in immortalization of T cells. We have shown also that the expression of Tax protected the mouse T-cell line CTLL-2 against apoptosis induced by deprivation of IL-2 and converted its growth from being IL-2 dependent to being IL-2 independent through the NF-kB pathway. In our study, we demonstrate that constitutive expression of survivin was associated with resistance to apoptosis after IL-2 deprivation in Tax-expressing CTLL-2 cells. Transient transfection assays showed that survivin promoter was transactivated by Tax, via the activation of NF-kB. Pharmacological NFkB inhibition resulted in suppression of survivin expression and caused apoptosis of Tax-expressing CTLL-2 cells. Our findings suggest that activated NF-kB signaling contributes directly to malignant progression of ATL by preventing apoptosis, acting through the prosurvival protein survivin. ' 2005 Wiley-Liss, Inc.

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. The highest endemic area of HTLV-1 carriers in Japan is located in Okinawa, and novel treatments are urgently needed in this area. We extracted fucoidan, a sulfated polysaccharide, from the brown seaweed Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan and examined its tumor-suppression activity against ATL. Fucoidan significantly inhibited the growth of peripheral blood mononuclear cells of ATL patients and HTLV-1-infected T-cell lines but not that of normal peripheral blood mononuclear cells. Fucoidan induced apoptosis of HTLV-1-infected T-cell lines mediated through downregulation of cellular inhibitor of apoptosis protein-2 and survivin and G1 phase accumulation through the downregulation of cyclin D2, c-myc, and hyperphosphorylated form of the retinoblastoma tumor suppressor protein. Further analysis showed that fucoidan inactivated NF-kappaB and activator protein-1 and inhibited NF-kappaB-inducible chemokine, C-C chemokine ligand 5 (regulated on activation, normal T expressed and secreted) production, and homotypic cell-cell adhesion of HTLV-1-infected T-cell lines. In vivo use of fucoidan resulted in partial inhibition of growth of tumors of an HTLV-1-infected T-cell line transplanted subcutaneously in severe combined immune deficient mice. Our results indicate that fucoidan is a potentially useful therapeutic agent for patients with ATL.

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I) and remains incurable. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, can be potentially effective by promoting cell apoptosis. Here we examined whether curcumin is effective in the treatment of ATL. Curcumin prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells but not of normal peripheral blood mononuclear cells. Curcumin induced cell cycle arrest by reducing the expression of cyclin D1, Cdk1 and Cdc25C and apoptosis by reducing the expression of XIAP and survivin. Most of these genes are known to be regulated by NF-jB, which plays a critical role in oncogenesis by HTLV-I. Curcumin suppressed constitutive active NF-jB of HTLV-Iinfected T-cell lines and primary ATL cells by inhibiting phosphorylation of IjBa. Curcumin also inhibited Tax-induced NF-jB transcriptional activity. However, curcumin-induced suppression of cell growth did not correlate with Tax expression level. Curcumin inhibited the growth of HTLV-I-infected T-cell tumors implanted subcutaneously in SCID mice. Our results indicate that curcumin has tumor-suppressive activity against ATL. ' 2005 Wiley-Liss, Inc.

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Although hepatic injury is reported in cases with dengue haemorrhagic fever and dengue shock syndrome, its mechanism remains poorly understood. Several findings suggest that dengue virus (DEN) induces apoptosis of hepatocytes in vivo. In this work, DEN type 2 (DEN-2) strain NGC was shown to induce apoptosis in the hepatic cell line HepG2, and infection of HepG2 cells was found to induce Apo2 ligand (Apo2L, also known as tumour necrosis factor-related apoptosis-inducing ligand or TRAIL) expression. Furthermore, Apo2L/TRAIL induced apoptosis in HepG2 cells, which expressed the Apo2L/TRAIL receptor DR5/TRAIL-R2 on their surface. Analysis of the Apo2L/TRAIL promoter revealed that this gene was activated by DEN-2 infection, whose responsive element was overlapping NF-kB-and Sp1-binding sites located at nt "75 to "65. The proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal (LLnL) inhibited Apo2L/TRAIL mRNA expression, and LLnL and anti-Apo2L/TRAIL antibody inhibited DEN-2-induced apoptosis. It was proposed that DEN infection promotes apoptosis partly through the induction of Apo2L/TRAIL expression. INTRODUCTIONDengue viruses (DENs), mosquito-borne flaviviruses, are major human pathogens affecting about 100 million individuals in tropical and subtropical regions of the world annually, and are classified into four serotypes (dengue virus types 1 to 4, designated here DEN-1, -2, -3 and -4) (Gubler, 1998). All four serotypes of DEN are capable of causing human disease with varying degrees of severity, ranging from asymptomatic infection or dengue fever to the devastating dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Cardinal signs of DHF and DSS include haemorrhage, abrupt onset of vascular leakage and shock, accompanied by severe thrombocytopenia and massive complement activation (Bokisch et al., 1973;Nimmannitya, 1987). In DHF and DSS, liver involvement is a characteristic disease sign (Bhamarapravati et al., 1967). Hepatic injury is similar to that of the early stages of yellow fever, with an increase in plasma transaminase levels, fatty changes in hepatocytes, Kupffer cell hyperplasia, and centrolobular and midzonal necrosis (Innis, 1995). The most characteristic sign is the presence of acidophilic, or Councilman, bodies, which are apoptotic bodies (Feldmann, 1997) and correspond to those seen in the liver of yellow fever patients. DEN antigens have been detected in both hepatocytes and Kupffer cells (Bhamarapravati et al., 1967;Couvelard et al., 1999;Hall et al., 1991;Kangwanpong et al., 1995;Rosen et al., 1989).Although the pathogenesis of DEN-related disease remains poorly understood, virus-induced cell death may be a crucial pathogenic event. Apoptotic cell death has been implicated as a cytopathological mechanism in response to DEN infection both in vitro and in vivo (Despres et al., 1996(Despres et al., , 1998. During the last stage of apoptosis, cells break up into apoptotic bodies, which are then eliminated by phagocytosis. It has been suggested that apoptosis is an innate de...

HTLV-I is

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Our findings suggest the role of the retrovirus in the development of autoimmune thyroid diseases in HTLV-I-infected patients.