Platelet-activating factor mediates endotoxin tolerance by regulating indoleamine 2,3-dioxygenase-dependent expression of the suppressor of cytokine signaling 3 [Signal Transduction]

Indoleamine 2, 3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We previously determined plateletactivating factor (PAF) protects mice against lipopolysaccharide (LPS)-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments in IDO+/+ and IDO-/- mice using an LPSinduced endotoxemia model and rated organ injury (neutrophil infiltration, and liver function). Using ELISA and Western blotting, we also investigated the mechanism of PAF-mediated endotoxin tolerance during endotoxemia. PAFmediated endotoxin tolerance was dependent on IDO in vivo and in vitro and was not observed in IDO-/- mice. JAK/STAT signaling, crucial for SOCS3 expression, was also impaired in the absence of IDO. In an IDO- and STATdependent manner, PAF mediated a decrease in interleukin-12 (IL-12), a dramatic increase of interleukin-10 (IL-10), and reduced mouse mortality. In addition, PAF attenuated LPS-mediated neutrophil infiltration into the lungs and interactions between neutrophil-like (THP-1) and endothelial cells (HUVECs). These results indicate PAF-mediated endotoxin tolerance is initiated via IDO and JAK/STAT-dependent expression of SOCS3. Our study has revealed a novel tolerogenic mechanism of IDO action and an important association between IDO and SOCS3 with respect to endotoxin tolerance.

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