UMLS:C0036690 - FACTA Search

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Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined by flow cytometry the expression of lipopolysaccharide (LPS) receptor CD14 molecule on monocytes after addition of LPS to human whole blood. Within 30 min LPS induced an increase in monocyte CD14 expression, peaking between 1 and 3 h and followed by a slow decrease. Maximal increase in anti-CD14 monoclonal antibody binding sites was estimated as twofold the basal value. This effect, already observed with very low concentrations of LPS (10 pg/ml), was dose dependent. Protein synthesis was not involved in the CD14 hyperexpression since it was not influenced by co-incubation with cycloheximide. Finally, LPS-induced up-regulation of monocyte CD14 was associated with an increased binding of fluoresceinated LPS. We conclude that LPS in whole blood up-regulates the expression of its own CD14 receptor on monocytes, a phenomenon that could be relevant to the pathogenesis of gram-negative sepsis.
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PMID:Lipopolysaccharide induces up-regulation of CD14 molecule on monocytes in human whole blood. 137 69

IL-4 has been found to affect the phenotype and a variety of functions of human monocytes and macrophages and has been discussed as a monocyte activating protein along with other cytokines, such as IL-1 and IL-6. In this study we compared the effects of the cytokines IL-1, IL-6, IL-4, and a combination of IL-1 and IL-6 on the expression of the CD14 antigen, the FcIIIg receptor molecule CD16 and the MHC-class II molecules HLA-DR and HLA-DP. These molecules represent characteristic monocyte surface markers. Furthermore, the CD14 molecule has been described as a surface antigen of high in vivo relevance representing an indirect receptor for LPS. We further analyzed the effect of IL-4 on monocytes and macrophages with respect to their accessory function to initiate T-lymphocyte proliferation. Human peripheral blood monocytes strongly express the antigen CD14 and maintain it as a stable surface molecule during their differentiation to macrophages. Flow cytometry analysis of cultured monocytes demonstrated that cells incubated in the presence of IL-4, but not IL-1 and/or IL-6 revealed a reduced expression of the CD14 antigen in a dose- and time-dependent manner. After 3 days IL-4 treated cells were virtually CD14-negative. At the same time the expression of the CD16 antigen (FcRIIIg) was also strongly reduced, whereas the treatment with IL-4 led to an increased expression of MHC class II antigens such as HLA-DR and HLA-DP. The spontaneous low expression of HLA-DQ antigen on monocytes was not affected by any of the cytokines. Functionally, IL-4 treated CD14-negative monocytes exhibited a more than 2-fold higher activity to stimulate an accessory cell-dependent T cell proliferation. This was found in a mitogenic assay and in MLC when compared to monocytes cultured in the absence of IL-4. These observations provide further evidence that IL-4 is a major modulator of monocyte surface antigen expression. Moreover, IL-4 has an enhancer-effect on monocytes as accessory cells and therefore may be of considerable importance as a regulatory factor during monocyte development to accessory cells. Inasmuch as the CD14 molecule functions as a receptor for LPS-binding protein, our results suggest that IL-4 might also play an important regulatory role in processes initiated by bacterial lipopolysaccharides during inflammation and sepsis.
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PMID:IL-4 decreases the expression of the monocyte differentiation marker CD14, paralleled by an increasing accessory potency. 171 65

Gram-negative bacterial septicemia is a common clinical syndrome resulting, in part, from the activation of phagocytic leukocytes by LPS. By using flow cytometry, we have characterized LPS-induced expression of the beta 2 integrin CD11b/CD18. After exposure to Salmonella minnesota R595 LPS, expression of neutrophil CD11b/CD18 is rapidly upregulated, beginning within 5 min and achieving a peak fluorescence (typically two- to threefold over base line) by 30 min. The increase in CD11b/CD18 expression was similar in kinetics and magnitude to that produced by FMLP, PMA, and human rTNF-alpha. Concentrations of LPS necessary to stimulate a response were as low as 1 ng/ml of R595 LPS; a maximal response was observed between 30 and 100 ng/ml. The upregulation of CD11b/CD18 due to LPS was not interrupted by protein synthesis inhibitors. A group of glucosamine disaccharide lipid A-like molecules: Rhodobacter sphaeroides lipid A, lipid IVA, KDO2IVA, and deacylated LPS were able to block the stimulatory effect of LPS. This inhibition was specific for the actions of LPS as stimulation of polymorphonuclear leukocytes (PMN) by FMLP, human rTNF alpha, PMA, and rewarming were not altered by the disaccharide inhibitors. PMN which were exposed to the specific disaccharide LPS antagonists and then washed, were refractory to stimulation by LPS. The monosaccharide lipid A precursor lipid X also blocked stimulation of neutrophils by LPS, although with a 100-fold reduction in potency. Unlike the disaccharide inhibitors, PMN exposed to lipid X were still responsive to LPS stimulation after washing. The PMN response to LPS was less sensitive in the absence of serum, although upregulation of CD11b/CD18 could still be seen using higher concentrations of LPS. Monoclonal antibody directed against CD14 (clone 3C10), also specifically inhibited LPS induced PMN CD11b/CD18 expression both in the presence and absence of serum. These findings support the hypothesis that LPS stimulates neutrophils by interacting with specific cellular receptors.
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PMID:Lipopolysaccharide-induced stimulation of CD11b/CD18 expression on neutrophils. Evidence of specific receptor-based response and inhibition by lipid A-based antagonists. 171 86

Infection occurring in patients suffering from severe trauma or burns often leads to hypotension, disseminated intravascular coagulation, multiorgan failure, and death. These latter pathophysiologic changes often are associated with Gram-negative sepsis and endotoxemia. Substantial progress has been made in understanding the effector mechanisms for endotoxin (LPS) action with the recognition of the importance of LPS-inducible products of cells of monocytic lineage in mediating LPS-induced injury. Here we will review recent evidence that supports a model for monocyte/macrophage activation by LPS that involves a plasma protein known as lipopolysaccharide binding protein (LBP) and the monocyte differentiation antigen, CD14.
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PMID:A new model of macrophage stimulation by bacterial lipopolysaccharide. 225 81

Vascular endothelium activated by endotoxin (lipopolysaccharide [LPS]) and cytokines plays an important role in organ inflammation and blood leukocyte recruitment observed during sepsis. Endothelial cells can be activated by LPS directly, after its interaction with LPS-binding protein and soluble CD14 in plasma. LPS-LPS-binding protein complexes in blood also interact with monocytes and neutrophils bearing glycosyl-phosphatidylinositol (GPI) anchored membrane CD14 (mCD14), promoting the release of cytokines such as tumor necrosis factor and interleukin 1 (IL-1). These molecules, in turn, have the capacity to activate endothelial cells providing an indirect pathway for LPS-dependent endothelial cell activation. In this work, we address the relative importance of the direct and the indirect pathway of in vitro LPS-induced human umbilical vein endothelial cell (HUVEC) activation. Substituting whole blood for plasma resulted in a 1,000-fold enhancement of HUVEC sensitivity to LPS. Both blood- and plasma-dependent enhanced activation of HUVEC were blocked with an anti-CD14 monoclonal antibody. Blood from patients with paroxysmal nocturnal hemoglobinuria, whose cells lack mCD14 and other GPI anchored proteins, was unable to enhance LPS activation of HUVEC above the level observed with plasma alone. IL-10, an inhibitor of monocyte release of cytokines, decreased the blood-dependent enhancement of HUVEC activation by LPS. Blood adapted to small doses of LPS was also less efficient than nonadapted blood in producing this enhancement. Addition of purified mononuclear cells to HUVEC or the transfer of plasma from whole blood incubated with LPS to HUVEC, duplicated the enhancement effect observed when whole blood was incubated with HUVEC. Taken together, these data suggest that the indirect pathway of LPS activation of endothelial cell is mediated by monocytes and mCD14 through the secretion of a soluble mediator(s). The indirect pathway is far more efficient than the direct, plasma-dependent pathway.
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PMID:A critical role for monocytes and CD14 in endotoxin-induced endothelial cell activation. 750 60

Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS), have been implicated in the activation of coagulation in sepsis and endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF) which, assembled with factor VII, initiates the blood coagulation cascades. In this study we investigated the mechanism of LPS recognition by monocytes, and the consequent expression of TF mRNA and TF activity. We also studied the inhibition of these effects of LPS by rBPI23, a 23-kD recombinant fragment of bactericidal/permeability increasing protein, which has been shown to antagonize LPS in vitro and in vivo. Human peripheral blood mononuclear cells, or monocytes isolated by adherence, were stimulated with Escherichia coli O113 LPS at physiologically relevant concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the presence of the serum protein LBP (lipopolysaccharide-binding protein), as shown by the potentiating effect of human recombinant LBP or serum. Furthermore, recognition of low amounts of LPS by monocytes was also dependent on CD14 receptors, because monoclonal antibodies against CD14 greatly reduced the LPS sensitivity of monocytes in the presence of serum or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited by rBPI23. The expression of tumor necrosis factor showed qualitatively similar changes. Considering the involvement of LPS-induced TF in the potentially lethal intravascular coagulation in sepsis, inhibition of TF induction by rBPI23 may be of therapeutic benefit.
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PMID:Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein. 751 3

Endotoxic shock is associated with a coagulopathy, organ failure, and death. Tissue factor (TF) expression by monocytes exposed to bacterial endotoxin (lipopolysaccharide [LPS]) may mediate the coagulopathy and contribute to the high mortality of this disease. We examined the role of the LPS-binding protein (LBP)/CD14 receptor pathway in the LPS induction of TF expression in human monocytic THP-1 cells and peripheral blood monocytes. In THP-1 cells, the threshold concentration of LPS required to induce TF activity in serum-free medium was reduced 20-fold by purified LBP, which also enhanced TF mRNA synthesis. Similarly, monocytes cultured in the presence of serum were induced to express TF antigen at LPS concentrations 100 times lower than monocytes cultured in serum-free medium. An anti-LBP monoclonal antibody indicated that this effect was dependent on the presence of LBP in serum. LPS/LBP induction of TF activity and TF antigen expression in these monocytic cells were also inhibited by an anti-CD14 monoclonal antibody, indicating a requirement for the CD14 receptor. Thus, we suggest that low levels of LPS (5 to 100 pg/mL) present during sepsis induce TF expression in monocytes via the LBP/CD14-dependent pathway.
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PMID:Role of the lipopolysaccharide (LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells. 751 85

CD14, a glycolipid-anchored membrane glycoprotein, acts as a high affinity lipopolysaccharide receptor on leukocytes. We previously reported that the Mono-Mac-6 cell line releases two different soluble forms of CD14 (sCD14) (Labeta et al., Eur. J. Immunol. 1993. 23: 2144). Here we show that the two sCD14, which we now refer to as sCD14 alpha (low M(r)) and sCD14 beta (high M(r)), are also synthesized and released by normal human monocytes and present in normal plasma. Their mechanism of release was examined by using the Mono-Mac-6 cell line, chinese hamster ovary cell (CHO)/CD14+ transfectants and plasma from paroxysmal nocturnal hemoglobinuria (PNH) patients. It was found that: (1) sCD14 beta is released faster than sCD14 alpha and that the release of the latter is a lengthy process. (2) Monensin blocked the biosynthesis of membrane-bound CD14 (mCD14) and sCD14, additionally, a 50-kDa CD14 polypeptide accumulated in the cell lysate, suggesting that the different forms of CD14 may have a common precursor. (3) Monensin also blocked the release of sCD14 alpha from surface-labeled cells, suggesting that conversion of mCD14 to sCD14 alpha involves a mechanism of endocytosis followed by exocytosis. Interestingly, (4) sCD14 alpha and sCD14 beta were detected in PNH plasma, indicating that sCD14 alpha may also derive from an endogenous pathway. (5) Phospholipase C-released CD14 was identical in size to mCD14, thus differed from sCD14 beta by approximately 2000, indicating that release of sCD14 beta involves further processing. (6) CHO cells transfected with a CD14 cDNA coding for an eight C-terminal amino acids shorter product released an sCD14 beta-like form; thus absence of the eight C-terminal amino acids prevented mCD14 expression but not the secretion of sCD14 beta. The characterization of sCD14 alpha and sCD14 beta reported here may be useful for better understanding of variations in sCD14 levels in pathological conditions and the contribution of each sCD14 in sepsis and other, as yet unknown functions.
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PMID:The two soluble forms of the lipopolysaccharide receptor, CD14: characterization and release by normal human monocytes. 752 57

LPS has been implicated in the pathogenesis of Gram-negative bacterial sepsis. Despite intensive efforts to define the LPS-signal transduction pathway, CD14 is the sole molecule clearly demonstrated to possess signaling capabilities. However, it remains unclear whether CD14 is the only LPS-signaling molecule expressed in phagocytes and how CD14-mediated signaling occurs. Compound SDZ 280.961 is a synthetic triacylated amino acid that structurally resembles the reducing sugar moiety of lipid A. SDZ 280.961 effectively stimulated TNF-alpha release from human PBMC. Co-incubation of PBMC with the specific LPS inhibitor Rhodobacter sphaeroides lipid A inhibited SDZ 280.961-mediated stimulation of TNF-alpha release, indicating that this analogue signals mononuclear cells via a LPS-activated signaling pathway. Induction of TNF-alpha release from mononuclear cells by SDZ 280.961 was strongly dependent on the presence of serum and was enabled by the presence of purified LPS-binding protein, characteristics of CD14-mediated signaling. In contrast, SDZ 280.961-mediated signaling was not inhibited by blocking anti-CD14 mAbs. A Chinese hamster ovary fibroblast line transfected with human CD14, which responds to LPS in a manner qualitatively similar to that of macrophage cell lines, failed to respond to SDZ 280.961. Taken together, these data suggest that the lipid A analogue SDZ 280.961 activates monocytes via a unique LPS-signal transduction pathway that appears to be independent of CD14.
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PMID:Acyclic analogue of lipid A stimulates TNF-alpha and arachidonate release via a unique LPS-signaling pathway. 752 28

Marked elevation of transforming growth factor-beta 1 (TGF-beta 1) has been demonstrated clinically following injury and in sepsis. While alterations in the monocyte binding site (CD14) for the lipopolysaccharide (LPS)-lipopolysaccharide binding protein (LBP) complex have been noted with exposure to LPS, immune complexes, gamma-interferon, and IL-4, it is not known whether TGF-beta 1 can alter CD14 expression. To study the effect of TGF-beta 1 on monocyte CD14 expression, human leukocytes were isolated from healthy donors with discontinuous gradient centrifugation and incubated at 37 degrees C for 2 and 24 hr with increasing doses of purified human platelet TGF-beta 1. Monocytes were immunofluorescently stained with monoclonal antibodies recognizing CD14 and CD16. The cells were analyzed by flow cytometry. At 2 hr, 50 ng/ml TGF-beta 1 significantly lowered CD14 expression (51%, P = 0.043). At 24 hr, there was no significant difference between cells stimulated by TGF-beta 1 and control cells. To confirm that TGF-beta 1 was active at 24 hr, we examined levels of CD16. CD16 expression was increased by 10 ng/ml of TGF-beta 1. These observations suggest that high physiologic concentrations of TGF-beta 1 cause early monocyte suppression of CD14. Thus, CD14 may be marker for the transition of monocytes to macrophages and TGF-beta 1 may be responsible for the down-regulation of CD14 expression observed in monocytes obtained from septic patients.
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PMID:Transforming growth factor-beta 1 lowers the CD14 content of monocytes. 752 45

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