Inflammation is a key event in the development of
liver cancer. We studied early inflammatory responses of Kupffer cells (KCs) and hepatocyte (HC) after
cancer initiation. The chemical
carcinogen N-nitrosomorpholine (NNM) was used in a rat model. We applied a comprehensive analytical strategy including metabolic labeling, 2-D PAGE, LC-MS/MS-based spot identification and shotgun proteomics and thus determined the rates of synthesis of individual
proteins, compared whole tissue with isolated constituent cells and performed in vivo to in vitro comparisons of NNM effects. NNM increased synthesis of overall and 138 individual
proteins identified in HC and/or KC, indicating reprogramming of metabolism favoring protection, repair and replacement of cell constituents in HC and KC. Secretome analysis by 2-D PAGE and shotgun proteomics of HC revealed the induction of
acute phase proteins, in case of KC of
proteases,
cytokines and
chemokines, indicating inflammatory effects. All responses were induced rapidly, independently of signals from other cells, and closely mimicked the pro-inflammatory and protective effects of
inflammation modulators LPS in KC and
IL-6 in HC. In conclusion, the
carcinogen NNM exerts pro-inflammatory effects in the liver, partially by direct activation of KC. The acute
inflammation and its protective component will enhance formation, survival and proliferation of initiated cells and may therefore act synergistically with the genotoxic action of the
carcinogen.