Clostridium difficile toxins influence hepatocyte protein synthesis through the interleukin 1 receptor

Hypothesis: Clostridium difficile toxins require interleukin 1 (IL-l) produ ction or a functioning IL-l receptor to elicit acute-phase protein producti on by murine hepatocytes. Design: Experimental study. Setting: Research laboratory at the DVA Medical Center, St Louis. Mo. Cells Studied: Hepatocytes prepared from normal mice, From knockout mice de ficient in IL-1 production due to loss of IL-1 converting enzyme, or from k nockout mice deficient in the IL-1 p80 receptor. Interventions: Cells were treated with lipopolysaccharide, a crude C diffic ile toxin extract, or purified C difficile toxins A or B for 24 hours in vi tro, then radiolabeled with S-35 methionine. Newly synthesized acute-phase proteins were identified by electrophoresis and autoradiography. Main Outcome Measurers: Synthesis of a 23-kd acute-phase protein in respons e to the various stimuli. Results: Lipoyolysaccharide, C difficile culture extract, and purified toxi ns A and B stimulated the synthesis of the 23-kd acute-phase protein by hep atocytes from normal mice and by hepatocytes from knockout mice deficient i n the IL-l converting enzyme. However, hepatocytes from knockout mice defic ient in the IL-1 p80 receptor failed to produce this acute-phase protein wh en treated with the C difficile toxins, although they responded fully to li popolysaccharide. Conclusions: Stimulation of acute-phase protein synthesis by C difficile to xins does not require IL-1 production, but does require a functioning IL-1 p80 receptor. This suggests that some of the actions of these toxins are me diated by this receptor.