Survival of all life fonns requires dynamic response to environmental change and challenge. In higher organisms such phenomena include defensive reн sponse to stress, injury, viruses, and pathogens. To mount effective responses, an organism requires a sensitive and rapidly acting system to detect and fight such potentially life-threatening circumstances. In the case of viruses and other microbiological pathogens, for example, the immune system is capable of recognizing these agents as foreign by their antigenic properties. To fight them, various immune cells are activated, differentiated, expanded, and summoned to relevant sites. Antibodies are synthesized and cell-mediated defenses actiн vated. To achieve this, recognition of an invading agent by T cells, B cells, macrophages, and endothelial cells must elaborate defined genetic programs, such as the induced synthesis of soluble mediators (cytokines, growth factors, chemokines) and their receptors. The genetic response, ie the signal-responн sive induction of gene expression, is mediated ultimately by factors that control the transcription of these genes. Among the various factors that contribute to the induction of these rapid-response genes, the transcription factor NF-KB stands out as a central, coordinating regulator. A vast and interrelated array of defense genes is regulated, at least in part, by a family of closely related dimeric complexes collectively referred to as NF-KB. Indeed, the association between induced cellular defense genes and NF-KB transcription factors dates at least as far back as insects in evolutionary tenns. Beyond playing a central role in defensive responses, NF-KB may modulate gene expression in various other situations that signal rapid gene expression. NF-KB and its regulators appear to function in growth control, as evidenced by mis-regulation of NF-KB genes encoding genes in certain tumors. A develн opmental role is indicated by the dorsal protein, a Drosophila homologue of vertebrate NF-KB factors. dorsal controls axial polarity in developing embryos in response to a positional cue.

The diversification of NF-KB during evolution into multiple genetically encoded polypeptides that assemble as homo-and heterodimers, and that bear unique and overlapping functional activities, as well as unique and overlapping expression patterns, portends wide and varied functional roles for this family of transcription factors. In addition to its role in expression of host cell genes, NF-KB has been usurped by various viruses, including the human immunoн deficiency virus, to mediate viral gene expression. NF-KB's most obvious characteristic is its rapid translocation from cytoн plasm to nucleus in response to extracellular signals. Under most circumн stances, these factors lie dormant in the cytoplasm of unstimulated cells, kept there by an inhibitory protein termed IKB. Many signals inactivate the inhibitor IKB, thereby allowing NF-KB to enter nuclei and rapidly induce coordinate