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Lipopolysaccharide (LPS) binding protein (LBP) plays an important role in regulating leukocyte responses to LPS. Remarkably, it may either augment these responses at low LBP concentrations or inhibit them at high concentrations. We previously reported that native high-density lipoprotein (HDL) augments human monocyte responses to LPS by suppressing the inhibitory activity of high concentrations of LBP, a process that occurs before HDL can inhibit the response by subsequently binding and neutralizing LPS. We now show that this novel activity is conferred largely by an HDL component protein, apolipoprotein (apo)A-II. Purified apoA-II was highly active in our assays. We also found that HDL from apoA-II-deficient mice was almost completely inactive, whereas the activities of HDLs that lacked apoA-I, apoC-I, apoE, or apoC-III were similar to that of wild-type HDL. Decreased activity was also observed in rabbit HDL, which is naturally deficient in apoA-II. Incorporating human apoA-II into rabbit HDL increased its activity to levels found in human HDL. Our investigation of the mechanism of apoA-II activity revealed that LBP promoted the formation of large LPS aggregates with low bioactivity and that apoA-II inhibited the formation of these aggregates without binding and directly inhibiting LPS bioactivity. Our results suggest a novel pro-inflammatory activity of apoA-II that may help maintain sensitive host responses to LPS by suppressing LBP-mediated inhibition. Our findings also raise the possibility that the decline of plasma apoA-II during sepsis may help control the response to LPS.

Apolipoprotein A-II augments monocyte responses to LPS by suppressing the inhibitory activity of LPS-binding protein