IN-VIVO HEPATOCYTE PROLIFERATION IS INDUCIBLE THROUGH A TNF AND IL-6-INDEPENDENT PATHWAY

Recent studies in mice harboring a targeted disruption of genes encodi ng TNF receptor 1 (TNFR-1) or Interleukin 6 (IL-6) suggested a critica l role for TNF and IL-6 in initiation of liver regeneration after 2/3 partial hepatectomy. However, hepatocyte proliferation can also occur following treatment with agents that do not induce tissue loss (primar y mitogens). To determine whether the above cytokines could also be in volved in mitogen-induced liver cell proliferation, we studied the hep atocyte proliferative response after treatment with primary mitogens i n mice knock-out for TNFR-1 or IL-6. Our results showed no difference in the proliferative response of the liver between the wild type and t he knock-out mice following treatment with the mitogens I,4-bis[2-(3,5 -dichloropyridyloxy)] benzene (TCPOBOP), or the peroxisome proliferato r, ciprofibrate, suggesting that TNF or IL-6 may not play a major role in this type of proliferation. Gel shift assay indicated that TCPOBOP -induced hepatocyte proliferation is not associated with activation of STAT3 transcription factor, a major target of IL-6 and other growth f actors/cytokines. Our results thus indicate that hepatocyte proliferat ion can be induced by at least two different pathways; compensatory re generation being TNF and IL-6-dependent, and mitogen-induced direct hy perplasia which does not require TNF or IL-6.