Extracellular ubiquitin inhibits the TNF-α response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness

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Abstract
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-α (TNF-α) and TNF-α mRNA expression from peripheral blood mononuclear cells (PBMNCs) in response to endotoxin in a dose-dependent manner. In contrast, the TNF-α 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-α response to endotoxin by ubiquitin. Elevated ubiquitin levels in serum were significantly correlated with a reduced TNF-α production. Antibodies to ubiquitin were able to (1) significantly increase (2- to 5-fold) the TNF-α 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-α production, and (3) partially neutralize the inhibitory effect of sepsis patients' serum on healthy donors' TNF-α production. Ubiquitin-depleted serum from trauma patients lost the inhibitory activity for TNF-α 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.