STAT proteins play critical roles in the signal transduction pathways for various cytokines. The type I interferons (IFNα/β) promote the DNA-binding activity of the transcription factors STAT1, STAT2, and STAT3. Although the requirement for STAT1 and STAT2 in IFNα/β signaling and action is well documented, the biological importance of STAT3 to IFN action has not yet been addressed. We found that STAT3 plays a critical role in signal transduction by IFNα/β. A human cell line that is resistant to the antiviral and antiproliferative activities of IFN but is still IFN-responsive by virtue of STAT1 and STAT2 activation was found to be defective in STAT3 activation and in induction of NF-κB DNA-binding activity. Expression of STAT3 in these resistant cells complemented these signaling defects and also markedly increased cellular sensitivity to the antiviral and antiproliferative effects of IFN. Because STAT3 is involved in the induction of NF-κB DNA-binding activity and in the induction of antiviral and antiproliferative activity, our results place STAT3 as an important upstream element in type I IFN signal transduction and in the induction of biological activities. Therefore, our results indicate that STAT1 and STAT2 are not the only STATs required for the expression of the key biological activities of IFNα/β.

With respect to conveying useful comparative information, current biological classifications are seriously flawed because they fail to (i) standardize criteria for taxonomic ranking and (ii) equilibrate assignments of taxonomic rank across disparate kinds of organisms. In principle, these problems could be rectified by adopting a universal taxonomic yardstick based on absolute dates of the nodes in evolutionary trees. By using procedures of temporal banding described herein, a simple philosophy of biological classification is proposed that would retain a manageable number of categorical ranks yet apply them in standardized fashion to time-dated phylogenies. The phylogenetic knowledge required for a time-standardized nomenclature arguably may emerge in the foreseeable future from vast increases in multilocus DNA sequence information (coupled with continued attention to phylogeny estimation from traditional systematic data). By someday encapsulating time-dated phylogenies in a familiar yet modified hierarchical ranking scheme, a temporal-banding approach would improve the comparative information content of biological classifications.

The cytokine macrophage migration inhibitory factor (MIF) has emerged to be an important regulator of the inflammatory response and is critically involved in the development of septic shock, arthritis, and glomerulonephritis. Although the biological activities of MIF are presumed to require a receptor-based mechanism of action, the protein is also a tautomerase and has a catalytically active N-terminal proline that is invariant in structurally homologous bacterial isomerases. This observation raises the possibility that MIF may exert its biological action via an enzymatic reaction. Physiologically relevant substrates for MIF have not been identified, nor have site-directed mutagenesis studies consistently supported the requirement for a functional catalytic site. Small molecule inhibitors of MIF's isomerase activity also have been developed, but none have been shown yet to inhibit MIF biological activity. We report herein that the iminoquinone metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), inhibits both the isomerase and the biological activities of MIF. The reaction between NAPQI and MIF is covalent and produces a NAPQI-modified MIF species with diminished cell binding activity and decreased recognition by anti-MIF mAb. These data are consistent with a model by which the NAPQI reacts with the catalytic Pro-1 of MIF to disrupt the integrity of epitope(s) critical to MIF's biological activity and point to the importance of the catalytic domain...