Dynamics of Gene Expression in Rat Hepatocytes under Stress

The response of cells to physical or biochemical stress involves concerted changes in the expression of a large number of genes encoding various functions. We have used a quantitative kinetic RTPCR technique to follow the dynamics of changes in transcription factor and acute-phase mRNA levels in cultured rat hepatocytes subjected to either elevated temperature (40 degrees C) or exposure to the inflammatory cytokine interleukin-6. The profiles of transcription factor gene expression displayed rapid and coordinate regulation, attainment of new steady-states, transitions in some instances from up-regulation to down-regulation (or vice versa), and, for elevated temperature, multiple spikes of up-regulation. Transcripts of acute-phase genes generally displayed relatively small changes during the first few hours followed by more significant changes over the course of tens of hours (elevated temperature) to days (IL-6 exposure). These observations are all consistent with the notion of genetic reprogramming due to a network of interacting transcription factor proteins and transcripts. We utilized a simple transcription/translation model incorporating autoregulation to describe the dynamics of transcription factor gene expression. This model successfully described key features of the transcription factor dynamics, most notably the multiple spikes observed after exposure to elevated temperature. The dynamics of gene expression are rich in information that, with considerably more study, may eventually be exploited to provide insights into the interplay of genetic networks in regulating a variety of cellular responses. (C) 2000 Academic Press