Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (T H 2) effector mechanisms leading to host protection against helminthic parasites remain elusive 1 . Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4-expressing memory CD4 + T cells that induced IL-4 receptor hi (IL-4R hi ) CD206 + alternatively activated macrophages 2 . In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths.Productive adaptive immune responses result in CD4 + T-cell polarization into effector phenotypes defined by differing cytokine milieus 3 . Helminth parasites and allergens induce T H 2 responses, including CD4 + T-cell interleukin (IL)-4 production promoting arginase-1 expression by alternatively activated macrophages (AAMacs) 4 . Although it is known that these AAMacs accumulate during asthmatic inflammation 5 and helminth parasite infections 2,4,6, 7 , and downregulate type 1 inflammation 2,4,6 , a protective role for them remains undefined.Infection of mice with the natural mouse gastrointestinal helminth parasite Heligmosomoides polygyrus triggers a highly polarized T H 2 response 1 . H. polygyrus infection is chronic with established adult worms; if parasites are cleared from the host's intestinal lumen, a rapid, protective T H 2 memory response operates against challenge infections 8 . Our studies examined early events in this memory response to H. polygyrus larvae developing in the intestinal submucosa and indicated that AAMacs have an important role in parasite expulsion. Fig. 1 online), with tissue-invading larvae developing into adults and migrating into the lumen at day 8 after inoculation ( Supplementary Fig. 1). To examine which stages of the protective memory response required CD4 + T cells, we administered CD4-specific antibody to mice to deplete CD4 + cells at specific intervals after secondary infection (Fig. 1a). Administration at early time points (days 0 and 7) resulted in increased worm burden (Fig. 1b), day 7 treatment had intermediate effects, and later treatments (days 9 or 11) had marginal effects, indicating that CD4 + T cells are required at early stages of a secondary infection for effective parasite expulsion. This implicated the adaptive immune response during larval development in the intestinal tissue as crucial for host protection. To further confirm that the memory response affects invasive larvae, we recovered muscularis-residing larvae from infected small intestines by using a Baermann apparatus 9 , which provokes premature larval evacuation of the tissue, as an indicator of health and mobility. Significantly fewer larvae were recovered from the tissues of m...

Not surprisingly, the death of a cell is a complex and well controlled process. For several decades, apoptosis, the first genetically programmed death process to be identified has taken centre stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Apoptosis has been extensively studied and its contribution to the pathogenesis of disease well documented. However, apoptosis does not function alone in determining the fate of a cell. More recently, autophagy, a process in which de novo formed membrane enclosed vesicles engulf and consume cellular components, has been shown to engage in complex interplay with apoptosis. As a result, cell death has been subdivided into the categories apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). The boundary between Type I and II cell death is not completely clear and as we will discuss in this review and perhaps a discrete difference does not exist, due to intrinsic factors among different cell types and crosstalk among organelles within each cell type. Apoptosis may begin with autophagy and autophagy can often end with apoptosis, inhibition or a blockade of caspase activity may lead a cell to default into Type II cell death from Type I.

We recently noted that low doses of sorafenib and vorinostat interact in a synergistic fashion to kill carcinoma cells by activating CD95, and this drug combination is entering phase I trials. The present studies mechanistically extended our initial observations. Low doses of sorafenib and vorinostat, but not the individual agents, caused an acidic sphingomyelinase and fumonisin B1-dependent increase in CD95 surface levels and CD95 association with caspase 8. Knock down of CD95 or FADD expression reduced sorafenib/vorinostat lethality. Signaling by CD95 caused PERK activation that was responsible for both promoting caspase 8 association with CD95 and for increased eIF2α phosphorylation; suppression of eIF2α function abolished drug combination lethality.

Background: A pool of the nuclear transcription factor Stat3 in the mitochondria (mitoStat3) controls respiration and Ras transformation. Results: Serine phosphorylation of mitoStat3 controls accumulation of reactive oxygen species and growth of breast cancer in mice. Conclusion:These results provide the first evidence for a mechanism by which mitoStat3 contributes to tumorigenesis. Significance: The data suggest new therapeutic approaches to treatment of breast cancer.

Purpose and Design: Mechanism(s) by which the multikinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat interact to kill hepatic, renal, and pancreatic adenocarcinoma cells has been defined. Results: Low doses of sorafenib and vorinostat interacted in vitro in a synergistic fashion to kill hepatic, renal, and pancreatic adenocarcinoma cells in multiple short-term viability (24-96 h) and in long-term colony formation assays. Cell killing was suppressed by inhibition of cathepsin proteases and caspase-8 and, to a lesser extent, by inhibition of caspase-9. Twenty-four hours after exposure, the activities of extracellular signal-regulated kinase 1/2, AKT, and nuclear factor-nB were only modestly modulated by sorafenib and vorinostat treatment. However, 24 h after exposure, sorafenib-and vorinostat-treated cells exhibited markedly diminished expression of c-FLIP-s, full-length BID, BCL-2, BCL-XL, MCL-1, XIAP, increased expression of BIM, and increased activation of BAX, BAK, and BAD. Expression of eIF2a S51A blocked sorafenib-and vorinostat-induced suppression of c-FLIP-s levels and overexpression of c-FLIP-s abolished lethality. Sorafenib and vorinostat treatment increased surface levels of CD95 and CD95 association with caspase-8. Knockdown of CD95 or FADD expression significantly reduced sorafenib/ vorinostat-mediated lethality. Conclusions: These data show that combined exposure of epithelial tumor cell types to sorafenib and vorinostat diminishes expression of multiple antiapoptotic proteins and promotes activation of the CD95 extrinsic apoptotic and the lysosomal protease pathways, and that suppression of c-FLIP-s expression represents a critical event in transduction of the proapoptotic signals from CD95 to promote mitochondrial dysfunction and death.