In this issue of The Journal of Experimental Medicine, Hud-son et al.(1) report on the identification of a cytokine, the macrophage migration inhibitory factor or MIF, that overcomes p53 function by suppressing its transcriptional activity, thus linking complex programs that govern proinflammatory response and cell fate. p53 has a key role in the regulation of cell growth and death, and its involvement in these regulatory systems may reflect its ability to respond to different cellular stress situations by inducing cell cycle arrest or apoptosis (see references 2–4 for reviews on the topic and below for more details on p53 function). When altered by germ line or somatic mutations, by aberrant patterns of expression, or through the inactivating potential of Mdm2 or certain viral oncoproteins, loss of wild-type p53 function is responsible for tumorigenesis and tumor progression (5–7). The relationship between certain chronic inflammatory conditions and cancer has been known for many years, and several postulates have been furnished to explain such an association (for recent reviews see references 8 and 9). The study of Hudson et al. provides a mechanistic connection between chronic inflammation and tumorigenesis. The authors used two independent functional screens to isolate genes bypassing p53-mediated growth arrest or apoptosis, which both yielded cDNAs encoding MIF. Three different biological assays were then pursued to assess p53 status after treatment with MIF. MIF was either directly tested by transducing it into different cells or, as MIF was originally characterized as an extracellular cytokine, it was added as a soluble factor. These experiments revealed that p53 continues to possess the same microanatomical nuclear localization and maintain similar levels of expression in control and MIF-treated cells. However, MIF partially suppresses p53-dependent transcriptional activity, as evidenced by the low levels of p21, cyclin G1, and Mdm2 observed in treated versus untreated cells. In the presence of MIF, Hudson et al. also observed suppression of apoptosis. Finally, murine fibroblasts treated with MIF have an extended life span, supporting the concept that MIF may, at least in part, overcome cellular senescence.

It is known that during tissue damage, lymphocytes and macrophages are recruited at sites of inflammation. MIF is released from T cells and macrophages, contributing to enhanced T cell activation and increased antimicrobial functions of macrophages. Besides these proinflammatory functions, activated macrophages also release reactive oxygen species. These, in turn, could induce macrophage apopto-