Endotoxin shock is the result of activation of the immune system by endotoxin/LPS, a component of Gram-negative bacteria. CD14, a GPI-anchored glycoprotein expressed strongly by monocyte/macrophages, is one of several receptors for endotoxin/LPS. The role of CD14 in bacterial-induced and LPS-induced shock was tested in CD14-deficient mice produced by gene targeting in embryonic stem cells. CD14-deficient mice were found to be highly resistant to shock induced by either live Gram-negative bacteria or LPS; however, at very high concentrations of LPS or bacteria, responses through non-CD14 receptors could be detected. Surprisingly, CD14-deficient mice also showed dramatically reduced levels of bacteremia, suggesting an unexpected role for CD14 in the dissemination of Gram-negative bacteria.

Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IkappaBzeta (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IkappaB family member Bcl-3 (refs 1-6). Transcription of IkappaBzeta is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IkappaBzeta is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IkappaBzeta-deficient cells show severe impairment of IL-6 production in response to a variety of TLR ligands as well as IL-1, but not in response to tumour-necrosis factor-alpha. Endogenous IkappaBzeta specifically associates with the p50 subunit of NF-kappaB, and is recruited to the NF-kappaB binding site of the IL-6 promoter on stimulation. Moreover, NF-kappaB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IkappaBzeta-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IkappaBzeta-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IkappaBzeta occurs earlier than transcription of these genes, some TLR/IL-1R-mediated responses may be regulated in a gene expression process of at least two steps that requires inducible IkappaBzeta.

PPI therapy more effectively prevented delayed bleeding from the ulcer created after ESD than did H2RA treatment.

Binding of the lipid A portion of bacterial lipopolysaccharide (LPS) to leukocyte CD14 activates phagocytes and initiates the septic shock syndrome. Two lipid A analogs, lipid IVA and Rhodobacter sphaeroides lipid A (RSLA), have been described as LPS-receptor antagonists when tested with human phagocytes. In contrast, lipid IVA activated murine phagocytes, whereas RSLA was an LPS antagonist. Thus, these compounds displayed a species-specific pharmacology. To determine whether the species specificity of these LPS antagonists occurred as a result of interactions with CD14, the effects of lipid IVA and RSLA were examined by using human, mouse, and hamster cell lines transfected with murine or human CD14 cDNA expression vectors. Several precursors and analogs of the toxic lipid A moiety from Escherichia coli LPS have been shown to inhibit LPS activation of lymphocytes, neutrophils, monocytes, and macrophages. By increasing the concentration of LPS relative to the concentration of antagonist, inhibition by these agents was overcome, suggesting that they competed with LPS for binding to a specific component of the LPS-signaling system. For example, Rhodobacter sphaeroides lipid A (RSLA) exhibited LPS antagonist properties in both murine (15-17) and human LPS-responsive cells (15,18). In contrast to RSLA, the tetraacyldisaccharide lipid A precursor, designated lipid IVA, inhibited LPS-induced activation of human cells (15,18,19) but acted as an LPS mimetic in murine cells (15,18), demonstrating a species-specific effect of these LPS-receptor antagonists.Kitchens et al. (20,21) reported that lipid IVA, when used in nanomolar concentrations under physiologic conditions, effectively blocked LPS-induced activation of human monocytes, whereas micromolar concentrations of lipid IVA were required to block specific binding of LPS to surface CD14. The difference between the concentration of LPS antagonists required to inhibit signal transduction compared to concentrations required to block specific binding of LPS to CD14 suggested that CD14 was not the cellular target for antagonists such as lipid IVA. Collectively, these findings are consistent with a model of signal transduction in which LPS-bound CD14 interacts with an as-yet-unidentified protein(s) present in limiting quantities on endotoxin-responsive cells that then induces a signal-transduction event across the plasma membrane. However, a definitive interpretation of these cellbinding studies (20,21) is complicated by the problems inherent with lipophilic and amphipathic ligands such as LPS. For Abbreviations: LPS, lipopolysaccharide; FBS, fetal bovine serum; NF-KB, nuclear factor KB; IFN-y, interferon -y; RSLA, Rhodobacter sphaeroides lipid A; GPI, glycosyl-phosphatidylinositol; EMSA, electrophoretic mobility-shift assay.