The role of Bcl-xL and nuclear factor-kappaB in the effect of taxol on the viability of dendritic cells

Taxol has been used effectively in cancer therapies. Our previous study demonstrated that taxol induced altered maturation and improved viability of dendritic cells (DCs). However, the effects of taxol on DC viability have not been fully elucidated. In the present study, flow cytometric analyses revealed that taxol treatment significantly increased the number of viable DCs and the expression levels of a representative anti-apoptotic protein Bcl-xL. Furthermore, mobilization of the p65 subunit of nuclear factor-kappaB (NF-kappaB) from the cytosol to the nucleus in DCs was observed by confocal microscopy. An inhibition assay using N-p-tosyl-L-phenylalanine chloromethyl ketone confirmed that NF-kappaB was intimately involved in the effects of taxol on DC viability. In addition, we investigated the mechanisms of taxol enhancement of DC viability. Since taxol is a popular anticancer agent used in clinic, this study may provide a rationale for the use of taxol in DC immunotherapy to treat cancer patients. Taken together, these results confirm that taxol increases DC viability, and this information may provide new insights for new clinical applications of both taxol and DCs.

The role of IL-12 in experimental Trypanosoma cruzi infection

Host resistance to Trypanosoma cruzi infection in dependent on both natural and acquired immune responses. During the early acute phase of infection in mice, natural killer (NK) cell-derived IFN-gamma is involved in controlling intracellular parasite replication, mainly through the induction of nitric oxide biosynthesis by activate macrophages. We have shown that IL-12, a powerful inducer of IFN-gamma production by NK cells, is synthesized soon after trypomastigote-macrophage interaction. The role of IL-12 in the control of T. cruzi infection in vivo was determined by treating infected mice with anti-IL-12 monoclonal antibody (mAb) and analyzing both parasitemia and mortality during the acute phase of infection. The anti-IL-12 mAb-treated mice had higher levels of parasitemia and mortality compared to control mice. Also, treatment of infected mice with mAb spectific for IFN-gamma or TNF-alpha inhibited the protective effect of exogenous IL-12. On the other hand, TGF-beta and IL-10 produced by infected macrophages inhibited the induction and effects of IL-12. Therefore, while IL-12, TNF-alpha and IFN-gamma correlate with resistance to T. cruzi infection, TGF-beta and IL-10 promote susceptibility. These results provide support for a role of innate immunity in the control of T. cruzi infection. In addition to its protective role, IL-12 may also be involved in the modulation of T. cruzi-induced myocarditis, since treatment of infected mice with IL-12 or anti-IL-12 mAb leads to an enhanced or decreased inflammatory infiltrate in the heart, respectively. Understanding the role of the cytokine produced during the acute phase of T. cruzi infection and their involvement in protection and pathogenesis would be essential to devise new vaccines or therapies.

Natural killer cells and interleukin-12 in patients with advanced cervical cancer under neoadvanced chemotherapy

Patients with advanced cervical cancer have deficient natural killer (NK) cell activity, usually as a consequence of tumor invasion, which results in tumor NK cell sequestration. The reason for the occurrence of such alterations in patients under chemotherapy is unknown. We evaluated the activity and number of NK cells and T cell subpopulations in ten patients before and three weeks after neoadjuvant chemotherapy (CT). The schedule used was cis-platinum (100 Mg/M2 per cycle) and bleomycin (15 mg/cycle), repeated every 28 days. Although there were similar levels of NK cells before and after CT in both groups, we observed greater cytotoxicity of peripheral blood lymphocytes and increased levels of CD4+ and CD8+ T cells (P<0.01) in five patients who presented a good clinical response when compared to the group with a poor response. IL- 12, known to increase NK cell activity when added to peripheral blood lymphocyte cultures, markedly increased lytic activity before and after CT only in the group with a good clinical response. These results suggest that NK cells from the poorly responding patient group express less lytic activity per NK cell and are insensitive to IL- 12 stimulation, probably as a result of reduced IL-12 receptor expression or a defective intracellular transduction mechanism. The present findings may be useful as a prognostic factor in clinical practice and also provide support for human clinical trials of IL- 12 and neoadjuvant CT for the treatment of malignant cervical tumors.