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

Interferon-gamma and other cytokines enhance macrophage (M phi) antimicrobial function and have been considered for therapeutic use in sepsis. Systemic sequelae of macrophage activation, however, are unclear. This study examined the effects of M phi activating cytokines (interferon-gamma [IFN-gamma] and interleukin-4 [IL-4]) and monoclonal antibodies directed against these cytokines in modulating the acute septic response. CFW/Swiss Webster mice (n = 345) received endotoxin (lipopolysaccharide [LPS]: 60 mg/kg body weight intraperitoneally) and were randomized to five treatment groups: IFN-gamma (10(4) units), IL-4 (10(4) units), IgG1 isotype antibody (TRFK5: 200 micrograms), anti-IFN-gamma (200 micrograms), or anti-IL-4 (200 micrograms) monoclonal antibodies (MAbs) given simultaneously or 2 hours after LPS. Animals were divided into two groups and studied for mortality or measurement of peritoneal M phi superoxide anion release (O2-), tumor necrosis factor (TNF), and IL-6 production 6 hours after administration of LPS +/- experimental regimens. Serum TNF and IL-6 also were assessed at 2 and 4 hours after LPS, respectively. Administration of LPS resulted in a 27% survival compared with 10% in the IFN-gamma and 13% in the IL-4 groups. Treatment with anti-IFN-gamma offered protection against LPS lethality (93%-100% survival, p less than 0.001 vs. other groups) when given either simultaneously or 2 hours after LPS. Anti-IFN-gamma also significantly decreased PM phi O-2 and TNF release. Thus anti-IFN-gamma may have an important role in the modulation of the acute septic response.
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PMID:Inhibition of macrophage-activating cytokines is beneficial in the acute septic response. 165 39

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

We studied in vitro functional parameters of peripheral blood B-lymphocytes from severely burned patients (n = 10; burn injuries ranging from 25 to 72% TBSA). While the number of B-cells remained unchanged, B-cell proliferation induced by Staphylococcus aureus strain Cowan I (SAC) was normal or even enhanced at early and late phases postburn, but showed a marked suppression during the second to fourth week. A similar pattern was observed for the pokeweed mitogen (PWM)- or SAC-stimulated synthesis of immunoglobulin M (IgM), whereas IgG production was decreased over the whole postburn period monitored. Cytokine (interleukin 4)-induced B-cell activation as indicated by the expression of the CD23 surface antigen was impaired throughout the second to fifth week. In parallel, the release of the proteolytic cleavage product sCD23 which represents a B-cell growth and differentiation factor was reduced. Our data provide evidence that activation, proliferation, and differentiation processes of B-lymphocytes are impaired in severely burned patients, which may contribute to their enhanced susceptibility to infection and sepsis.
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PMID:Studies on B-lymphocyte dysfunctions in severely burned patients. 223 6

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

We have previously demonstrated that staphylococcal enterotoxins contribute to arthritis and mortality during staphylococcal infection. To further explore the mechanism by which bacterial superantigens contribute to the pathogenesis of Staphylococcus aureus septicemia, T-cell receptor V beta 3 transgenic (TGV beta 3) mice and nontransgenic (non-TG) littermates were inoculated intravenously with S. aureus AB-1, which produces large amounts of staphylococcal enterotoxin A, which specifically reacts with T-cell receptor V beta 3. Within 9 days after inoculation, 85% of the TGV beta mice died, compared with 31% of their non-TG littermates (P < 0.01). The high mortality of TGV beta 3 mice was accompanied by elevated bacterial burdens in the blood, spleen, and kidneys. The in vivo kinetics of cytokine mRNA expression was studied by an in situ hybridization technique. Staphylococcal infection gave rise to increased expression of interleukin 1 beta (IL-1 beta) mRNA and sparsely expressed tumor necrosis factor alpha (TNF-alpha), IL-4, and IL-10 mRNAs in both groups. Gamma interferon mRNA expression increased on day 3 and was maintained at a detectable level in the late phase of infection in TGV beta 3 mice, in contrast to non-TG mice. Impressively, significantly higher expression of TNF-beta mRNA in TGV beta 3 mice was noted throughout the course of infection than in non-TG littermates. These findings suggest that overproduction of TNF-beta and gamma interferon, the Th1 cytokines, may play a crucial role in the pathogenesis of septicemia caused by enterotoxin-secreting staphylococci.
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PMID:Overexpression of the T-cell receptor V beta 3 in transgenic mice increases mortality during infection by enterotoxin A-producing Staphylococcus aureus. 759 Oct 86

Cytokines, released by T cells, participate in inflammation and produce tissue injury. Excess production of cytokines such as interleukins (ILs) and tumor necrosis factor (TNF) is believed to be involved in the pathobiology of conditions such as septicemia and septic shock, collagen vascular diseases, glomerulonephritis etc. On the other hand, prostaglandins (PGs) are known to modulate inflammation, immune response, and T-cell response to antigens. But relatively little information is available on the effects of PGs and PG precursors on the release of cytokines. Here the authors present data which suggests that PGs including thromboxane B2 (TXB2) and their precursors such as dihomo-gamma linolenic acid (DGLA), arachidonic acid (AA) and eicosapentaenoic acid (EPA) can inhibit T-cell proliferation and influence their ability to secrete IL-2, IL-4, IL-6 and TNF in vitro. These results may have relevance to the use of PG-precursors in various inflammatory conditions including collagen vascular diseases.
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PMID:Effect of prostaglandins and their precursors on the proliferation of human lymphocytes and their secretion of tumor necrosis factor and various interleukins. 793 85

The mechanism by which PG of the E series (PGE) promote murine B lymphocyte IgE production was investigated. We previously reported that PGE, and other agents that increase intracellular cAMP, synergize with IL-4 and LPS to induce IgE and IgG1 production while inhibiting IgM and IgG3 synthesis. These data suggested that PGE may promote IL-4-induced class switching, but the mechanism by which PGE increases IgE synthesis remained obscure. We report here that 1) PGE increases (up to 14-fold) the number of splenic B cells secreting IgE, even though PGE mildly inhibits proliferation. 2) PGE acts on sorted surface IgM positive B cells, consistent with PGE acting on uncommitted B cells to promote class switching to IgE. 3) PGE synergizes with IL-4 to induce germline epsilon transcripts, demonstrating that PGE acts at the level of transcription in cells that have not yet switched to IgE. 4) In the presence of PGE, rearranged mature V(D)J epsilon mRNA transcripts can be detected earlier and at higher levels than with IL-4 and LPS alone. Taken together, these data provide strong evidence that PGE synergizes with IL-4 and LPS to direct isotype switching to the epsilon heavy chain gene in purified B lymphocytes. PGE is a potentially important in vivo immunoregulator, particularly with regard to IgE production and the genesis of allergy. In support of this hypothesis, there are numerous clinical conditions (hyper-IgE, trauma, sepsis, Hodgkin's lymphoma, arthritis) in which overproduction of PGE is coincident with elevated IgE titers.
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PMID:Prostaglandin E2 promotes B lymphocyte Ig isotype switching to IgE. 799 35

Although studies indicate that polymicrobial sepsis produces marked depression in lymphocyte functions, it remains unclear whether this dysfunction is due to the chronic exposure of immune cells to endotoxin (ETX; a product of the gram-negative bacterial cell wall) at levels typically encountered in the septic state. The aim of this study, therefore, was to determine whether the changes in lymphokine release seen during polymicrobial sepsis are comparable to those observed with chronic ETX infusion. To assess this, splenocytes were harvested from C3H/HeN mice (ETX-sensitive) at 1 or 24 hr following cecal ligation and puncture (CLP; to induce polymicrobial sepsis), Sham CLP (Sham), or laparotomy followed by peritoneal implantation of a mini-osmotic pump which delivered either saline vehicle (Sal-pump) or ETX (ETX-pump; 0.025 micrograms lipopolysaccharide/25 g body wt/24 hr). Splenocytes were then stimulated with concanavalin A (2.5 micrograms/ml/48 hr) and their capacity to release interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-10 was determined by bioassay or ELISA. The results indicated that there were no changes in lymphokine release capacity at 1 hr after CLP or ETX-pump implantation. However, prolonged sepsis (i.e., at 24 hr) caused a marked suppression of IL-2 and IFN-gamma release (immune-enhancing lymphokines characteristic of Th1-cells), while enhancing the release of immunosuppressive Th2-cell products IL-4 and IL-10. Chronic exposure to ETX at a level comparable to that seen in CLP caused no depression in lymphokine (IL-2/IFN-gamma) release. This implies that a bacterial component other than ETX mediates the differential alterations observed in lymphokine release during prolonged polymicrobial sepsis.
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PMID:Polymicrobial sepsis but not low-dose endotoxin infusion causes decreased splenocyte IL-2/IFN-gamma release while increasing IL-4/IL-10 production. 801 14

Injury has been hypothesized to cause inflammation through systemic release of lipopolysaccharide and pro-inflammatory cytokines, but this has proved difficult to demonstrate in humans. We looked for evidence of an inflammatory pattern of cytokine gene expression by peripheral blood mononuclear cells (PBM) in six polytraumatized patients (ISS = 25 +/- 8) upon ER admission, and in six matched healthy controls. PBM tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-4, IL-6, IL-10, and interferon (IFN)-gamma message was assessed by semi-quantitative reverse-transcription polymerase chain reaction. No increase in expression of any of the pro-inflammatory cytokines (tumor necrosis factor-alpha, IL-1 beta, or IL-6) was found after trauma, and IFN-gamma tended to decrease. Of the immunosuppressive cytokines, IL-10 expression increased 5-fold (p < .05) but no change in IL-4 was discerned. This pattern is fundamentally different from the cytokine expression patterns expected with sepsis or exposure to lipopolysaccharide. These findings are inconsistent with the occurrence of systemic endotoxemia and subsequent global immunocyte activation early after trauma.
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PMID:Human peripheral mononuclear cells do not show proinflammatory patterns of cytokine transcription in early trauma: a preliminary report. 856 51

Certain cytokines, particularly gamma-interferon (IFN) and interleukin (IL)-2 associated with TH1 cell function, have been shown to play a role in allograft rejection. One paradigm for long-term allograft acceptance involves TH2 cytokine predominance (IL-4 and IL-10). We describe two renal allograft recipients for whom immunosuppression was discontinued due to serious sepsis and who maintained stable renal function over 2-6 months without immunosuppression. During this time, there were higher levels of both IFN-gamma and IL-10 in the peripheral blood than in stable control kidney transplant recipients on immunosuppression. In one of the patients, levels of IL-10 fell, while those of IFN-gamma remained persistently elevated. This was associated with biopsy-proven rejection. Although peripheral blood cytokine levels may not reflect intragraft events, these data are consistent with an allograft protective role for IL-10 offsetting that of IFN-gamma in both patients off immunosuppression.
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PMID:Association of interleukin-10 with rejection-sparing effect in septic kidney transplant recipients. 862 96


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