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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0918.
Submitted March 27, 2002
Accepted October 16, 2002
Extracellular ubiquitin inhibits the TNF response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness
Matthias Majetschak*, Ulrich Krehmeier, Mark Bardenheuer, Christof Denz, Michael Quintel, Gregor Voggenreiter, and Udo Obertacke
Klinik fuer Unfallchirurgie, Universitaetsklinikum Mannheim, Mannheim, Germany
Klinik fuer Anaesthesiologie, Universitaetsklinikum Mannheim, Mannheim, Germany
* Corresponding author; email: mmajetschak{at}med.miami.edu.
Ubiquitin is suggested to play a key role in essential intracellular functions, such as heat shock response, protein breakdown and regulation of immune responses. Ubiquitin has also been detected in the extracellular space, but the function and biological significance is almost enigmatic. We describe a new function of extracellular ubiquitin and show that extracellular ubiquitin specifically inhibits ex vivo TNF secretion and TNF mRNA expression of peripheral blood mononuclear cells in response to endotoxin in a dose dependent manner, whereas the TNFa response to zymosan or Staphylococcus aureus as well as the interleukin (IL)-6 and IL-8 response to endotoxin was unaffected by ubiquitin. Measurement of ubiquitin serum levels showed a significant 5-7-fold increase in sepsis and trauma patients, to the level required for inhibition of the PBMNCs TNF response to endotoxin by ubiquitin. Elevated ubiquitin serum levels were significantly correlated with a reduced TNF production. Antibodies to ubiquitin were able to 1. significantly increase the TNF response to endotoxin in trauma and sepsis patients' whole blood 2-5-fold, 2. to completely neutralize the inhibitory effect of trauma patients' serum on healthy donors TNF production and 3. to partially neutralize the inhibitory effect of sepsis patients' serum on healthy donors TNF production. Ubiquitin depleted trauma patients serum lost the inhibitory activity for TNF production, whereas extracted endogenous ubiquitin exerts the inhibitory activity. The results demonstrate that extracellular ubiquitin acts as a cytokine-like protein with anti-inflammatory properties and indicate, that extracellular ubiquitin is involved in the regulation of immunodepression in critical illness.
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