Cytokine and chemokine networks: pathways to antiviral defense.

The complex interplays between cytokines and chemokines are emerging as key communication signals in the shaping of innate and adaptive immune responses against foreign pathogens, including viruses. In particular, the virus-induced expression of cytokine and chemokine profiles drives the recruitment and activation of immune effector cells to sites of tissue infection. Under the conditions of infection with murine cytomegalovirus (MCMV), a herpesvirus with pathogenic potential, early immune functions are essential in the control of virus replication and virus-induced pathology. The coordinated MCMV-induced cytokine and chemokine responses promote effective natural killer (NK) cell recruitment and function, and ultimately MCMV clearance. The studies highlighted in this chapter illustrate in vivo pathways mediated by innate cytokines in regulating chemokine responses that are vital for localized antiviral defenses.

IFN-gamma enhances paclitaxel-induced apoptosis that is modulated by activation of caspases 8 and 3 with a concomitant down regulation of the AKT survival pathway in cultured human keratinocytes.

The aim of this study was to investigate the molecular effects of paclitaxel and IFN-gamma on cultured human keratinocyte cells (HaCaT) assessing the induction of both the apoptotic pathway and cell survival signals. Cellular cytotoxicity assays were performed by MTT dye assay. Caspases 8, 3 and AKT (Ser473 and Thr308 residues) were assessed by Western blot analysis. Morphological characteristics were examined by Wright stain analysis. Paclitaxel reduced keratinocyte growth in a 3-day bioassay with an effective ED(50) of 6-600 ng/ml. A large variation in ED(50) can be attributed to the asynchronous population of cells. Paclitaxel treatment induced activation of the AKT survival pathway in a time-dependent manner. The down-regulation of AKT signal was preceded by the subsequent activation of caspases 8 and 3 leading to apoptosis. These results indicate that paclitaxel activates both the PI3-K/AKT cell survival pathway followed by induction of apoptotic signals in cultured human keratinocytes. The induction of apoptosis in paclitaxel-treated cells is enhanced by coadministration of IFN-gamma. The synergistic effect of these two agents on HaCaT cells relies on a pathway involving caspases 8 and 3, with activity increasing by 48 h. Collectively, our data indicate that i) paclitaxel-induced apoptosis is enhanced by IFN-gamma; ii) the down-regulation of PI3-K/AKT survival pathway may help potentiate the apoptotic effects of paclitaxel and iii) the apoptotic signaling pathways are initiated with the activation of caspases 8 and 3 activities.