scholarly journals Septin: a factor in plasma that opsonizes lipopolysaccharide-bearing particles for recognition by CD14 on phagocytes.

1992 ◽  
Vol 176 (3) ◽  
pp. 719-727 ◽  
Author(s):  
S D Wright ◽  
R A Ramos ◽  
M Patel ◽  
D S Miller
Keyword(s):  
Neutralizing Antibodies ◽  
Polymorphonuclear Leukocytes ◽  
Protein Species ◽  
Opsonic Activity ◽  
Coated Particles ◽  
Leukocyte Integrins ◽  
Single Protein ◽  
Normal Human ◽  
Necrosis Factor ◽  
Lps Binding

We have previously reported that lipopolysaccharide (LPS) binding protein (LBP) opsonizes endotoxin (LPS) for recognition by CD14 on phagocytes. Here we show that normal human plasma contains high titers of an activity that also binds LPS (Re, 595) and mediates recognition by CD14. Opsonization of LPS-coated particles with plasma enables the particles to be bound by phagocytes. Further, opsonization with plasma also enables subnanogram-per-milliliter concentrations of LPS to induce dramatic alterations in the function of leukocyte integrins on polymorphonuclear leukocytes and to induce secretion of tumor necrosis factor by monocytes, suggesting that opsonization by factors in plasma may be important in responses of cells to endotoxin. The opsonic activity in plasma appears distinct from LBP since it is not blocked by neutralizing antibodies against LBP. Surprisingly, the opsonic activity of plasma is not present in a single protein species, but at least two species must be combined to observe activity. Further, the opsonic activity of plasma for LPS is blocked by addition of protease inhibitors, suggesting that proteolytic activity or activities are required for opsonization. These properties are suggestive of the action of a protease cascade, but opsonic activity of plasma is not affected by blockade or depletion of either the complement or clotting cascades. We propose the name "septin" to describe this novel LPS-opsonizing activity in plasma.

scholarly journals Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS.

1994 ◽  
Vol 180 (3) ◽  
pp. 1025-1035 ◽  
Author(s):  
M M Wurfel ◽  
S T Kunitake ◽  
H Lichenstein ◽  
J P Kane ◽  
S D Wright
Keyword(s):  
Binding Protein ◽  
Endotoxic Shock ◽  
High Density Lipoproteins ◽  
Human Neutrophils ◽  
Leukocyte Integrins ◽  
Apolipoprotein A ◽  
Biologic Activity ◽  
Normal Human ◽  
Lines Of Evidence ◽  
Lps Binding

Lipoproteins isolated from normal human plasma can bind and neutralize bacterial lipopolysaccharide (LPS) and may represent an important mechanism in host defense against gram-negative septic shock. Recent studies have shown that experimentally elevating the levels of circulating high-density lipoproteins (HDL) provides protection against death in animal models of endotoxic shock. We sought to define the components of HDL that are required for neutralization of LPS. To accomplish this we have studied the functional neutralization of LPS by native and reconstituted HDL using a rapid assay that measures the CD14-dependent activation of leukocyte integrins on human neutrophils. We report here that reconstituted HDL particles (R-HDL), prepared from purified apolipoprotein A-I (apoA-I) combined with phospholipid and free cholesterol, are not sufficient to neutralize the biologic activity of LPS. However, addition of recombinant LPS binding protein (LBP), a protein known to transfer LPS to CD14 and enhance responses of cells to LPS, enabled prompt binding and neutralization of LPS by R-HDL. Thus, LBP appears capable of transferring LPS not only to CD14 but also to lipoprotein particles. In contrast with R-HDL, apoA-I containing lipoproteins (LpA-I) isolated from plasma by selected affinity immunosorption (SAIS) on an anti-apoA-I column, neutralized LPS without addition of exogenous LBP. Several lines of evidence demonstrated that LBP is a constituent of LpA-I in plasma. Passage of plasma over an anti-apoA-I column removed more than 99% of the LBP detectable by ELISA, whereas 31% of the LBP was recovered by elution of the column. Similarly, the ability of plasma to enable activation of neutrophils by LPS (LBP/Septin activity) was depleted and recovered by the same process. Furthermore, an immobilized anti-LBP monoclonal antibody coprecipitated apoA-I. The results described here suggest that in addition to its ability to transfer LPS to CD14, LBP may also transfer LPS to lipoproteins. Since LBP appears to be physically associated with lipoproteins in plasma, it is positioned to play an important role in the neutralization of LPS.

scholarly journals Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide.

1993 ◽  
Vol 178 (6) ◽  
pp. 2207-2211 ◽  
Author(s):  
M A Cassatella ◽  
L Meda ◽  
S Bonora ◽  
M Ceska ◽  
G Constantin
Keyword(s):  
Tumor Necrosis Factor ◽  
Neutralizing Antibodies ◽  
Polymorphonuclear Leukocytes ◽  
Tumor Necrosis ◽  
Interleukin 10 ◽  
Second Phase ◽  
Endogenous Release ◽  
Human Polymorphonuclear Leukocytes ◽  
Necrosis Factor

In this study we have examined the effects of interleukin 10 (IL-10) on polymorphonuclear leukocytes (PMN), and found that it is a potent inhibitor of tumor necrosis factor (TNF), IL-1 beta, and IL-8 secretion triggered by lipopolysaccharide (LPS). Cytokine production by phagocytosing PMN was also inhibited by IL-10, but to a lesser extent than the LPS-induced production. As shown by Northern blot analysis, IL-10 diminished the levels of TNF, IL-1 beta, and IL-8 mRNAs late after the onset of stimulation of PMN with LPS. In addition, we provide evidence that the kinetics of LPS-induced IL-8 production by PMN is composed of two distinct phases. Specifically, our experiments demonstrated that in the first phase, the production of IL-8 is a process directly induced by LPS that lasts for some hours. After this early wave, a second phase begins that is sustained and leads to an elevated production of IL-8 that appears to be due to the endogenous release of TNF and IL-1 beta. This second wave can in fact be blocked by anti-TNF and anti-IL-1 beta neutralizing antibodies, and by IL-10 as the consequence of its downregulatory effects on TNF and IL-1 beta release. Taken together, these findings identify novel biological actions of IL-10 as a suppressor of the inflammatory response.

scholarly journals Release of tumor necrosis factor by human polymorphonuclear leukocytes

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1405-1409 ◽  
Author(s):  
JY Djeu ◽  
D Serbousek ◽  
DK Blanchard
Keyword(s):  
Tumor Necrosis Factor ◽  
Polymorphonuclear Leukocytes ◽  
Tumor Necrosis ◽  
Polymorphonuclear Neutrophils ◽  
Opportunistic Fungi ◽  
Produce Tumor Necrosis Factor ◽  
Human Polymorphonuclear Leukocytes ◽  
Block Protein Synthesis ◽  
Granular Lymphocytes ◽  
Necrosis Factor

Abstract Evidence is presented that human polymorphonuclear neutrophils (PMN) can be induced to produce tumor necrosis factor (TNF). Other investigators have previously reported that TNF has been induced from macrophages by bacteria and, more recently, from natural killer cells by certain tumor cells. Our laboratory has reported that the opportunistic fungi, Candida albicans, can induce TNF, not only from human monocytes, but also from Percoll-fractionated large granular lymphocytes. We now report that incubation of PMN with C albicans for 3 hours was sufficient for detection of TNF release, and peak induction was observed at 8 to 18 hours. This release was inhibitable by actinomycin D, an inhibitor of RNA synthesis, as well as by emetine and cycloheximide, which block protein synthesis. The TNF produced by PMN was neutralized by specific monoclonal antibodies against human TNF. These results represent an important finding that TNF production is a normal response of PMN to stimulation by fungi such as C albicans and suggest that the release of TNF may be related to autocrine activation of PMN effector function to control Candida growth.

scholarly journals Inflammatory cytokines induce synthesis and secretion of gro protein and a neutrophil chemotactic factor but not β2-microglobulin in human synovial cells and fibroblasts

1989 ◽  
Vol 259 (2) ◽  
pp. 585-588 ◽  
Author(s):  
E E Golds ◽  
P Mason ◽  
P Nyirkos
Keyword(s):  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Chemotactic Factor ◽  
Synovial Cells ◽  
Necrosis Factor Alpha ◽  
Normal Human ◽  
Neutrophil Chemotactic Factor ◽  
Factor Alpha ◽  
Beta 2 Microglobulin ◽  
Necrosis Factor

Exposure of human synovial cells and fibroblasts in monolayer culture to interleukin 1 results in prominent secretion of proteins with Mr values of 6000 and 7000. By N-terminal sequence analysis, the Mr-6000 protein is identified as the protein encoded by a recently described gro mRNA. The Mr-7000 protein is identical to a neutrophil chemotactic factor released from monocytes. Stimulation of normal human fibroblasts with tumour necrosis factor alpha also results in expression and secretion of these two proteins. In addition to these cytokine-induced proteins, we have identified beta 2-microglobulin as an Mr-8000 protein constitutively secreted by synovial cells.

The Role of Nuclear Factor-kappaB and Melanogenesis in Tumor Necrosis Factor-Alpha-Induced Apoptosis of Normal Human Melanocytes

2002 ◽  
Vol 15 (5) ◽  
pp. 321-329 ◽  
Author(s):  
Jing Shang ◽  
Jürgen Eberle ◽  
Christoph C. Geilen ◽  
Amir M. Hossini ◽  
Lothar F. Fecker ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Necrosis Factor Alpha ◽  
Human Melanocytes ◽  
Normal Human ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1

1994 ◽  
Vol 14 (10) ◽  
pp. 6561-6569
Author(s):  
L Klampfer ◽  
T H Lee ◽  
W Hsu ◽  
J Vilcek ◽  
S Chen-Kiang
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Normal Human ◽  
Factor Alpha ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

scholarly journals Effect of soluble interleukin-6 receptor α and interleukin-6 secreted by polymorphonuclear leukocytes on tumor necrosis factor-α expression and its production by peripheral blood mononuclear cells

2002 ◽  
Vol 11 (5) ◽  
pp. 325-328 ◽  
Author(s):  
E. Jablonska
Keyword(s):  
Interleukin 6 ◽  
Polymorphonuclear Leukocytes ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Interleukin 6 Receptor ◽  
Factor Α ◽  
Necrosis Factor

Background: It has recently been shown that soluble interleukin-6 receptor (sIL-6R) alone or complexed with interleukin (IL)-6, besides their regulatory role in a wide variety of both normal and abnormal biologic reactions mediated by IL-6, could be an effective stimulator of the cell function.Aims: The key question of the present study is whether the sIL-6Rα or sIL-6R with IL-6 released by polymorphonuclear leukocytes (PMN) can influence cytokine secretion such as tumor necrosis factor-α (TNF-α) by peripheral blood mononuclear cells (PBMC), which together with PMN develop the inflammatory and immune response of a host.Methods: Cells were isolated from heparinized whole blood of healthy persons. The PMN were cultured for 1 h at 37°C in 5% CO2. After incubation, the culture supernatant of PMN was removed and was added to PBMC. The PBMC were cultured for 1 h at 37°C in the same conditions. In the culture supernatants and lysates of PMN, we examined the concentrations of sIL-6R by enzyme-linked immunosorbent assay (ELISA). TNF-α was measured at both protein and mRNA levels. Protein levels were determined by ELISA. To examine TNF-α mRNA expression, we isolated mRNA from PBMC after culture, using TRIZOL Reagent. The quantity of mRNA TNF-α was determined by the Quantikine mRNA assay.Results and conclusion: The results obtained revealed that sIL-6R with IL-6 secreted by PMN may play a regulatory role in the immune response by modulating the TNF-α expression and its production by PBMC. This may have a significant influence on an early phase of the inflammation and other reactions mediated by TNF-α.

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