Tumor necrosis factor/cachectin (TNF) is a potent pleiotropic cytokine implicated in a number of pathological conditions including septic shock and cachexia (Beutler and Cerami 1986;Beutler 1990). In mice and humans, TNF is synthesized by activated monocytes mainly as a 26 kd propeptide which is proteolytically cleaved to a 17 kd secreted protein bearing cytolytic activity towards a host of cell-types (Kriegler et al. 1988). The leader sequence of TNF is inordinately long (76 and 79 amino acids in humans and mice, respectively) and well-conserved relative to analogous regions in other peptide hormones (Pennica et al. 1987). Perhaps related to these features of the leader sequence, TNF is biologically active both as a secreted protein and as an integral membrane protein in which the C-terminus is extracellular and theN-terminus is intracellular (Perez et al. 1990). In addition, alternative proteolytic cleavage results in different forms (active and inactive) of both membrane-bound and secreted molecules (Kriegler et al. 1990). Human and mouse TNF proteins appear to utilize different alternative proteolytic cleavage sites (Cseh and Beutler 1989;Kriegler et al. 1990) possibly due to species-specific amino acid residues in the vicinity of the normal cleavage site.
Genes encoding TNF and a related cytokine, lymphotoxin (LT), reside within the major histocompatibility complex (MHC; Spies et al. 1986;Mtiller et al. 1987). Due in part to the possible species-specific regulation of TNF and owing to our interests in evolution of MHC region genes, we have undertaken an analysis of the TNF gene from Peromyscus leucopus (family Cricetidae). The