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(American Journal of Pathology. 2003;163:465-476.)
© 2003 American Society for Investigative Pathology

Tumor Necrosis Factor-{alpha} Acts as a Complete Mitogen for Primary Rat Hepatocytes

Heather A. Iocca* and Harriet C. Isom*{dagger}

From the Departments of Microbiology and Immunology* and Pathology,{dagger} Milton S. Hershey Medical Center, The Penn State College of Medicine, Hershey, Pennsylvania

The cytokine tumor necrosis factor (TNF)-{alpha} has previously been shown to prime hepatocytes to a state of replicative competence, but has not been shown to act as a complete mitogen for these cells. In the present study we have altered our previously described long-term dimethyl sulfoxide culture system to exclude all known hepatocyte mitogens from the culture media and enable us to directly examine the effects of TNF-{alpha} on primary rat hepatocytes. We have shown that cells maintained under these culture conditions retain the biochemical and morphological features of well-differentiated hepatocytes. Treatment with TNF-{alpha} induced DNA synthesis relative to control, to a level not significantly different from that induced by the known hepatocyte mitogen, epidermal growth factor (EGF). Maximal DNA synthesis was induced by treatment with 250 U/ml TNF-{alpha} for 24 hours. Mitotic figures were observed in cultures treated with TNF-{alpha} or EGF but not in untreated controls. Treatment of cultures with TNF-{alpha}, but not EGF, induced activation of both nuclear factor-{kappa}B p50 homodimers and p50/p65 heterodimers. DNA synthesis induced by TNF-{alpha} was inhibited by treatment with transforming growth factor-ß. Based on the results of our studies, we conclude that TNF-{alpha} acts as a complete mitogen for rat hepatocytes.




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