No abstract

LPS binding protein (LBP) and CD14 play key roles in promoting innate immunity to Gram-negative bacteria by transferring LPS to the signaling receptor complex, MD-2/Toll-like receptor 4 (TLR4). LBP and soluble CD14 (sCD14) can also inhibit responses to LPS by mechanisms that depend on their concentration and environment; during acute inflammation and infection, their concentrations increase in plasma and extravascular fluids. Whereas low concentrations of LBP enhance responses to LPS, high LBP concentrations can inhibit LPS bioactivity in vitro and in vivo. sCD14 also inhibits cell responses by diverting LPS from membrane-bound CD14 (mCD14) and by promoting LPS efflux from cell-surface mCD14 and transferring it to plasma lipoproteins. In vivo studies support the hypothesis that sCD14 has systemic anti-inflammatory effects, whereas in the tissues it may have pro-inflammatory effects that increase resistance to bacteria. Likewise, LBP increases resistance to Gram-negative bacteria by rapidly triggering pro-inflammatory responses to LPS. Thus, the dual stimulatory and inhibitory mechanisms of sCD14 and LBP may benefit the infected host by promoting inflammation in local sites, where it is needed, while at the same time preventing potentially detrimental systemic responses to LPS.

SummaryThe induction of cachectin/tumor necrosis factor (TNF) synthesis by bacterial endotoxins is a process that entails activation at several levels . Cachectin/TNF gene transcription is accelerated, leading to rapid accumulation ofmP NA within the macrophage cytosol . In addition, translational derepression occurs, leading to far more efficient message utilization . Through the use of posttranscriptional reporter constructs, we now demonstrate that certain agents capable of inhibiting cachectin/TNF biosynthesis operate through different mechanisms. In RAW 264.7 macrophages, pentoxifylline blocks cachectin/TNF mRNA accumulation but has no effect upon the efficiency of reporter mRNA translation. Dexamethasone, on the other hand, has only a modest effect on cachectin/TNF mkNA accumulation, but strongly impedes translational derepression . Combined application of dexamethasone and pentoxifylline to macrophages causes a greater suppression of cachectin/TNF biosynthesis than can be achieved by either agent alone. These findings suggest that the signaling pathway activated by endotoxin is branched, and that selective inhibition of different parts of the pathway may be achieved through the use of distinct agents .