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Clostridium difficile Toxins Influence Hepatocyte Protein Synthesis Through the Interleukin 1 Receptor
John E. Mazuski, MD, PhD;
Erik M. Grossmann, MD;
James G. Norman, MD;
Woody Denham, MD;
Ninder Panesar, PhD;
Marc J. Shapiro, MD;
Rodney L. Durham, MD;
Donald L. Kaminski, MD;
Walter E. Longo, MD
Arch Surg. 2000;135:1206-1211.
Hypothesis Clostridium difficile toxins require interleukin 1 (IL-1) production or a functioning IL-1 receptor to elicit acute-phase protein production 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 deficient in IL-1 production due to loss of IL-1 converting enzyme, or from knockout mice deficient in the IL-1 p80 receptor.
Interventions Cells were treated with lipopolysaccharide, a crude C difficile toxin extract, or purified C difficile toxins A or B for 24 hours in vitro, then radiolabeled with 35S methionine. Newly synthesized acute-phase proteins were identified by electrophoresis and autoradiography.
Main Outcome Measures Synthesis of a 23-kd acute-phase protein in response to the various stimuli.
Results Lipopolysaccharide, C difficile culture extract, and purified toxins A and B stimulated the synthesis of the 23-kd acute-phase protein by hepatocytes from normal mice and by hepatocytes from knockout mice deficient in the IL-1 converting enzyme. However, hepatocytes from knockout mice deficient in the IL-1 p80 receptor failed to produce this acute-phase protein when treated with the C difficile toxins, although they responded fully to lipopolysaccharide.
Conclusions Stimulation of acute-phase protein synthesis by C difficile toxins 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 mediated by this receptor.
From the Department of Surgery, DVA Medical Center (Drs Mazuski and Longo), the Department of Surgery, Theodore Cooper Surgical Research Institute, Saint Louis University School of Medicine, St Louis, Mo (Drs Mazuski, Grossman, Panesar, Shapiro, Durham, Kaminski, and Longo); and the Department of Surgery, University of South Florida, Tampa (Drs Norman and Denham).
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