Immunology Select

The inflammatory response—characterized by release of cytokines such as TNFa and IL-1b and infiltration of infected or injured tissue by macrophages and neutrophils—is the first line of defense against infection by pathogens. Although an early inflammatory response is beneficial in stemming the tide of infection, a prolonged response may result in severe illness or even death. For example, the 1918 Spanish influenza virus was lethal because it triggered a ''cytokine storm'' that resulted in severe lung damage. An inappropriate and prolonged inflammatory response to normal nonpathogenic gut bacteria is a cause of Crohn's disease. Meanwhile, insidious low-level inflammation in the tumor microenvironment aids and abets tumor cells in their quest to become metastatic. Understanding the triggers of inflammation and the signaling pathways involved in cytokine production and immune cell mobilization will be essential for developing thera-peutics to treat diseases caused by a runaway inflammatory response. Inflammation in the tumor microenvironment—characterized by the infiltration of macrophages and the release of proinflam-matory cytokines such as TNFa—is a powerful driver of tumor formation and metastasis. The ability of tumor cells to detach from their microenvironment and migrate to other locations is reminiscent of the change that takes place during embryogen-esis when epithelial cells become more fibroblast-like and start to migrate. This process, termed the epithelial-to-mesen-chymal transition (EMT), is characterized by loss of expression of a surface marker called E-cadherin that enables cells to adhere to the substratum. The transcription factor Snail is responsible for repressing expression of E-cadherin. Reporting in Cancer Cell, Wu et al. (2009) now pinpoint Snail as a principal culprit in the inflammation-driven metastasis of tumor cells. They discovered that the normally labile Snail protein becomes stabilized in response to TNFa released by macrophages loitering at the invasive edge of epithelial tumors. The stable Snail protein then switches on genes required for instigation of the EMT program, enabling epithelial tumors to acquire a more mesenchymal phenotype that facilitates their detachment and migration into the circulation. Snail is normally phosphorylated by GSK3b and is then ubiquitinated and degraded by the proteasome, but how does Snail become stabilized? The authors show that TNFa switches on expression of the master transcription factor NF-kB, which then activates a gene encoding CSN2, a component of the COP9 signaling complex (signal-osome) that regulates ubiquitin ligases. The authors speculate that Snail may bind to the signalosome shielding itself from phosphorylation or that it may be deubiquitinated by …