The ability of transcription factors to bind DNA and modulate gene transcription is tightly regulated in normal cells. Specific intracellular signal transduction pathways regulate transcription factor activity through modification of key residues and domains within the transcription factor (1). These intracellular signaling systems transduce extracellular signals from the cell surface to the nucleus, where they are integrated at the level of transcription factor activity (Figure 1). The signaling pathways are highly diverse yet display an extraordinary degree of specificity for a given transcription factor or transcription factor family. The identification and molecular cloning of multiple regulatory enzymes that control key steps of these signal transduction pathways have sparked a search for novel therapeutic agents (2).

A number of transcription factor families, including those for activator protein 1 (AP-1)/activating transcription factor 2 (ATF2), nuclear factor B (NF-B), nuclear factor of activated T cells (NF-AT), signal transducer and activator of transcription (STAT), p53, and nuclear hormone receptors (Figure 1), have been implicated as critical regulators of gene expression in the setting of inflammation. Their members, upstream activators, and target genes are listed in Table 1. In the following sections the different classes of transcription factors and signal transduction pathways will be discussed in the context of their potential roles in rheumatic disease.