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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0918.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1882-1890
IMMUNOBIOLOGY
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
From the Department of Trauma Surgery, University
Hospital Mannheim, Faculty of Clinical Medicine Mannheim of the
Ruprecht-Karls University Heidelberg, Mannheim, Germany;
and Department of Anaesthesiology, University Hospital Mannheim,
Faculty of Clinical Medicine Mannheim of the Ruprecht-Karls University
Heidelberg, Mannheim, Germany.
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 biologic
significance is unclear. We describe a new function of extracellular
ubiquitin and show that extracellular ubiquitin specifically inhibits
ex vivo secretion of tumor necrosis factor- (TNF-) and TNF-
mRNA expression from peripheral blood mononuclear cells (PBMNCs) in response to endotoxin in a dose-dependent manner. In contrast, the
TNF- response to zymosan or Staphylococcus aureus as
well as the interleukin-6 (IL-6) and IL-8 responses to endotoxin were unaffected by ubiquitin. Measurement of serum ubiquitin levels showed a
significant 5- to 7-fold increase in sepsis and trauma patients, to the
level required for inhibition of the PBMNC TNF- response to
endotoxin by ubiquitin. Elevated ubiquitin levels in serum were
significantly correlated with a reduced TNF- production. Antibodies to ubiquitin were able to (1) significantly increase (2- to
5-fold) the TNF- response to endotoxin in whole blood from trauma
and sepsis patients, (2) completely neutralize the inhibitory effect of
trauma patients' serum on healthy donors' TNF- production, and (3)
partially neutralize the inhibitory effect of sepsis patients' serum
on healthy donors' TNF- production. Ubiquitin-depleted serum from
trauma patients lost the inhibitory activity for TNF- production,
whereas extracted endogenous ubiquitin exerts the inhibitory activity.
The results demonstrate that extracellular ubiquitin acts as a
cytokinelike protein with anti-inflammatory properties and
indicate that extracellular ubiquitin is involved in the regulation of
immunodepression in critical illness.
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