REGULATORY MECHANISMS OF HOST RESPONSIVENESS TO ENDOTOXIN (LIPOPOLYSACCHARIDE)

During Gram-negative endotoxemia, precise regulation of monocyte/macrophage (M-phi) responsiveness to lipopolyssaccharide (LPS) is critical to preserve host defense while avoiding complications such as organ failure and death. We will discuss regulation of LPS-M-phi interactions by LPS-binding plasma proteins and by LPS-induced changes in M-phi responsiveness. Upon exposure to plasma, LPS binds to either lipoproteins or LPS-binding protein (LBP; a 60-kilodalton glycoprotein with a high-affinity binding site for the lipid A moiety of rough and smooth LPS). The LPS-LBP complex stimulates the M-phi by binding to its cellular receptor, CD14 (a monocyte/M-phi-specific, phosphatidylinositol-anchored surface glycoprotein). Pretreatment of whole blood with anti-CD14 monoclonal antibody reduces the responsiveness of monocytes to LPS [determined by tumor necrosis factor-alpha (TNF-alpha) release] at least 10-fold. Similarly, cellular responsiveness to LPS is diminished at least 100-fold by depletion of plasma LBP with anti-LBP antibody. Compared to LPS-LBP induction of TNF-alpha, LPS-lipoprotein complexes are as much as 10,000-fold less active. Thus, partitioning of LPS between LBP and lipoproteins markedly influences M-phi responsiveness to LPS. LPS also directly induces M-phi hyporesponsiveness to itself by a process known as adaptation; exposure of M-phi to less-than-or-equal-to 100 pg LPS/ml (subthreshold for TNF induction) for 6-9 reduces the sensitivity of the M-phi to subsequent challenge up to 1,000-fold, so that 1-mu-g/ml rather than 1 ng/ml of LPS is required for maximal induction of TNF-alpha. LPS-adapted M-phi are specifically unresponsive to LPS (rough or smooth), yet remain fully responsive to heat-killed Staphylococcus aureus. The LPS-induced increase in steady state levels of TNF mRNA characteristic of control M-phi is not observed in adapted M-phi. This is not due to increased mRNA degradation or to autocrine inhibition of M-phi function by secretory products. Exposure of LPS-adapted M-phi to LBP increases the sensitivity of these cells to LPS. Thus, multiple pathways regulate host responsiveness to LPS and establish the balance between defense and injury.