Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alpha-1-antitrypsin (AT) is one of several alpha-globulins which have been shown to be inhibitors of human peripheral blood monocyte TNF secretion in vitro. AT deficiency states exist, within which individuals of either the PiSS or PiZZ phenotype have reduced hepatocyte and mononuclear phagocyte AT secretion when compared to normal PiMM subjects. Here we have compared the capacity of peripheral blood monocytes of all three phenotypes to respond to both enhancers and inhibitors of TNF secretion. All monocytes exposed to lipopolysaccharide (LPS), interferon-gamma (IFN-gamma) and endotoxin, PGE2, transforming growth factor-beta 1, whole plasma alpha-globulins, purified AT and IL-6 responded equally with respect to the secretion of TNF. Our findings show that the regulation of TNF secretion in leukocytes from AT deficient humans is normal and suggest that defective AT secretion alone does not result in the aberrant regulation of TNF secretion.
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PMID:Regulation of tumor necrosis factor secretion in leukocytes from alpha-1-antitrypsin deficient humans. 170 19

The macrophage scavenger receptor, a 220-kDa trimeric membrane glycoprotein, mediates the internalization of modified forms of low density lipoprotein (LDL) such as acetyl-LDL and oxidized-LDL and thus is likely to play a key role in atheroma macrophage foam cell formation. In addition, recent evidence suggests that the scavenger receptor may be an important macrophage binding site for lipopolysaccharide involved in lipopolysaccharide scavenging by macrophages. However, little is known about the regulation of this important receptor. We now report that the induction of scavenger receptor activity (as measured by acetyl-LDL stimulation of intracellular cholesterol esterification) seen in phorbol ester-differentiated THP-1 human macrophages was completely suppressed to the level seen in undifferentiated THP-1 monocytes by picomolar concentrations of transforming growth factor-beta 1 (TGF-beta 1). 125I-Acetyl-LDL degradation was inhibited in a dose-dependent manner by TGF-beta 1, with maximal inhibition (approximately 70%) occurring at 24 pM TGF-beta 1. Scatchard analysis revealed that TGF-beta 1 treatment resulted in a approximately 2-fold decrease in receptor number, and Northern blot analysis of RNA isolated from differentiated THP-1 macrophages demonstrated approximately 2-fold less scavenger receptor mRNA in TGF-beta 1-treated cells compared with that in macrophages not treated with TGF-beta 1. Since TGF-beta 1 is thought to be present in both atherosclerotic and inflammatory lesions, the above findings may have physiological relevance regarding the regulation of atheroma foam cell formation and/or the regulation of lipopolysaccharide clearance by macrophages.
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PMID:Transforming growth factor-beta 1 inhibits scavenger receptor activity in THP-1 human macrophages. 174 79

The viability of normal bone marrow myeloid precursor cells induced by interleukin-6 (IL-6) or IL-1 alpha and the ability of IL-6 and IL-1 alpha to induce the formation of colonies of granulocytes, macrophages, or megakaryocytes in densely seeded bone marrow cultures was suppressed by transforming growth factor-beta 1 (TGF-beta 1). Induction of normal bone marrow colony formation by IL-3 was much less sensitive to TGF-beta 1, and there was little or no effect of TGF-beta 1 on colony formation induced by macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF). In different clones of myeloid leukemic cells, TGF-beta 1 suppressed differentiation induced with IL-6, IL-1 alpha, or lipopolysaccharide (LPS), but did not suppress differentiation induced with IL-3 or GM-CSF. The effect of TGF-beta 1 on differentiation of the leukemic cells can be dissociated from its effect on cell growth. TGF-beta 1 suppressed the production of IL-6 in normal bone marrow cells cultured with IL-1 alpha and the production of IL-6 and GM-CSF in leukemic cells cultured with IL-1 alpha or LPS. The suppression of IL-6 production can explain the suppression by TGF-beta 1 of the effects of IL-1 alpha and LPS that are mediated by IL-6. TGF-beta 1 also suppressed differentiation in clones of myeloid leukemic cells induced with differentiation factor/leukemia inhibitory factor and tumor necrosis factor. In different leukemic clones TGF-beta 1 suppressed or enhanced induction of differentiation with dexamethasone. The results show that TGF-beta 1 can selectively control the activity of different molecular regulators of normal and leukemic hematopoiesis.
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PMID:Selective regulation of the activity of different hematopoietic regulatory proteins by transforming growth factor beta 1 in normal and leukemic myeloid cells. 220 8

The secretion of tumor necrosis factor (TNF) by human peripheral blood mononuclear cells was suppressed by either whole human plasma alpha-globulins or purified alpha 1-acid-glycoprotein, alpha 1-antitrypsin and alpha 2-macroglobulin in a concentration-dependent manner. alpha 1-Antitrypsin was found to be the most suppressive of the purified proteins tested and completely blocked TNF release at concentrations above 1.25 mg/ml. Both alpha 1-acid glycoprotein and alpha 1-antitrypsin blocked TNF secretion by leukocytes which were simultaneously stimulated with either recombinant human interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS). IFN-gamma- and LPS-activated cells were also susceptible to suppression mediated by these two alpha-globulins and the inhibition produced by 5 mg/ml alpha 1-antitrypsin was greater than that caused by either 1 microM prostaglandin E2 or 10 ng/ml transforming growth factor-beta 1. The level of TNF mRNA in TNF-secreting and alpha-globulin-suppressed cells was examined and found to be equal in both groups. The suppressive effect of whole alpha-globulins was confined to the inhibition of TNF secretion and these plasma proteins had no effect on the cytolytic activity of the recombinant cytokine as measured on murine L-929 target cells. Thus the alpha-globulins, which are a major fraction of the circulating plasma proteins, may function in TNF homeostasis by controlling TNF secretion without inhibiting the biological activity of the released cytokine.
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PMID:Alpha-globulins suppress human leukocyte tumor necrosis factor secretion. 247 79

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

Interleukin-11 (IL-11), a newly-identified cytokine produced by stromal cells, elevates platelet counts in neonatal rats in vivo and synergizes in vitro with IL-3 in supporting murine megakaryocyte colony formation and stimulating hematopoietic stem cells. Megakaryocytopoiesis is also enhanced by other colony-stimulating factors (CSFs), including IL-3, IL-6, and Steel factor (SLF). Dysregulation of neonatal thrombopoiesis predisposes newborns to develop thrombocytopenia during sepsis, despite increased circulating pools of committed thrombopoietic progenitors in newborn cord blood compared with adult. We previously reported reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), and IL-3 from stimulated cord mononuclear cells, but increased expression of SLF in human umbilical vein endothelial cells (HUVEC). Therefore, we hypothesized that IL-3, IL-6, and SLF might modulate megakaryocytopoiesis by inducing IL-11 expression, and newborns might express altered levels of IL-11 mRNA expression during activated conditions, contributing to the difference in circulating colony-forming unit-megakaryocyte (CFU-Meg) cord and adult blood. Phorbol myristate acetate (PMA) induced a twofold greater increase in IL-11 mRNA expression in neonatal fibroblasts (NFb) compared with adult fibroblasts (AFb), and a 3.6-fold greater increase in HUVEC than human adult aorta endothelial cells (HAEC) by Northern blot analysis. PMA also induced a threefold greater increase in IL-11 protein production in NFb than AFb. Physiologic agonists IL-1 alpha, transforming growth factor-beta 1 (TGF-beta 1), and TGF-beta 2 triggered upregulation of IL-11 mRNA expression in both NFb and AFb. However, IL-3, IL-6, PIXY321 (a GM-CSF-IL-3 fusion protein), and SLF failed to upregulate IL-11 mRNA expression from the basal level, while macrophage-colony stimulating factor (M-CSF) mRNA was significantly induced. These data suggest that the hematopoietic effect of IL-6, SLF, and IL-3 on megakaryocytopoiesis is probably not mediated by secondary IL-11 mRNA expression. Similarly, inflammatory agonists IL-1 beta, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) alone did not upregulate IL-11 expression from the basal level in endothelial cells, whereas intracellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 were strongly induced. Minimal basal IL-11 expression was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in NFb, AFb, HUVEC and HAEC. The quantitative RT-PCR assay also verified that IL-1 beta and TNF-alpha-stimulated HUVEC and HAEC, and IL-3- and IL-6-stimulated NFb and AFb only expressed minimal levels of IL-11 mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of interleukin-11 protein and mRNA expression in neonatal and adult fibroblasts and endothelial cells. 752 67

Bone marrow stromal cells produce cytokines that are essential for the proliferation and differentiation of hematopoietic stem and progenitor cells. Thus, regulation of cytokine production by bone marrow accessory cells is a critical aspect of stromal cell regulation of hematopoiesis. We have investigated the effect of two cytokines that have been demonstrated to modulate factor production by non-marrow accessory cells (i.e., transforming growth factor-beta 1 [TGF-beta 1] and interleukin-4 [IL-4]) on the induced expression of cytokine mRNA in a bone marrow-derived, cloned, murine stromal cell line +/+/-.LDA11. We showed that +/+/-.LDA11 cells can be induced with lipopolysaccharide (LPS), IL-1 alpha, or interferon-gamma (IFN-gamma) to express mRNA for monocyte chemoattractant protein-1 (MCP-1/JE), IFN-inducible protein-10 (IP-10), stem cell factor (SCF), and macrophage colony-stimulating factor (M-CSF) but not for IL-1 alpha, IL-3, or tumor necrosis factor-alpha (TNF-alpha). The expression of MCP-1/JE and IP-10 mRNA by these inducers was potentiated by TGF-beta 1 and IL-4. The augmentation by TGF-beta 1 of both mRNAs induced with IL-1 alpha was maximum when applied to the cells concurrently with the inducer; the IFN-gamma-induced expression of mRNAs was augmented even if the addition of TGF-beta 1 was delayed. Similarly, IL-4 potentiation of both mRNAs by either inducer progressively increased as the time between exposure to the inducer and exposure to IL-4 increased. Neither modulator altered the time course of mRNA expression by either inducer. TGF-beta 1- and IL-4-mediated augmentation of MCP-1/JE mRNA by IL-1 alpha or IFN-gamma was partially reversed by cycloheximide (CHX), whereas potentiation of IP-10 by either modulator remained unaffected. Increase in the stability of mRNA transcripts by TGF-beta 1 or IL-4 does not appear to play a role in the enhanced accumulation of mRNA in the presence of the modulators. These findings support a role for TGF-beta 1 and IL-4 as critical regulatory molecules in production of MCP-1 and IP-10 chemokines by stromal cells.
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PMID:Induction of chemokine mRNA in bone marrow stromal cells: modulation by TGF-beta 1 and IL-4. 776 3

In previous studies, we showed that interleukin-4 (IL-4) suppressed porcine (p) macrophage superoxide production and that the mechanism of suppression involved down-regulation of the superoxide-generating enzyme NADPH oxidase heavy-chain 91-kDa subunit mRNA (gp91-phox) expression. In order to examine the effect of IL-4 on expression of the gene encoding the porcine NADPH oxidase light-chain 22-kDa subunit (p22-phox), we cloned the p22-phox cDNA from a macrophage library. The p22-phox cDNA is 786 bp in length and contains a 576-bp open reading frame which predicts a primary translation product of 192 amino acids (aa). Comparison of the porcine and human 22-phox cDNAs showed a high degree of similarity between the two species in their nucleotide (85%) and deduced aa (83%) sequences. as well as in their hydropathy profiles. Notable features, including a high proline content and an iron-coordinating His94, are conserved in both the porcine and human 22-Phox. A single species of mRNA of about 1 kb was detected in macrophages. The mRNA levels remained unchanged in cells treated with lipopolysaccharide (LPS) or with IL-4 at various concentrations from 0-50 ng/ml. Prolonged treatment with LPS or IL-4 did not enhance the effect of these substances on p22-phox mRNA expression. The effect of IL-4 on p22-phox mRNA expression was also compared with another immunosuppressive cytokine, transforming growth factor-beta 1 (TGF beta 1). No change in mRNA expression was found in the cells with or without TGF beta 1 treatment. The results indicated that the heavy and light chains of NADPH oxidase are independently regulated by IL-4 in macrophages.
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PMID:Cloning and expression of the gene encoding the porcine NADPH oxidase light-chain subunit (p22-phox). 795 70

We have previously reported that culture of human peripheral blood leukocytes with interleukin-2 (IL-2) triggers the secretion of mediators which induce fibroblast proliferation and collagen synthesis. In addition, fibrogenic cytokines (transforming growth factor-beta 1 (TGF beta 1) and platelet-derived growth factor (PDGF) A and B chain) are present in the peritoneal fluid of patients undergoing intraperitoneal immunotherapy (IL-2-activated killer cells and IL-2) who go on to develop peritoneal adhesions. To determine the role of IL-2 in the formation of these adhesions, we chose to investigate whether IL-2 can induce the expression of fibrogenic cytokine genes in resident rat peritoneal macrophages. Cells were cultured with or without IL-2 or lipopolysaccharide (LPS) and expression of PDGF A chain, PDGF B chain, and TGF beta 1 mRNAs was determined. PDGF A and B chain mRNAs are minimally expressed in macrophages prior to stimulation and are induced within 2 hours of treatment with IL-2. In contrast, TGF beta 1 mRNA is constitutively expressed and can not be upregulated. The studies suggest that peritoneal macrophage-derived PDGF plays a critical role in the production of adhesions in patients receiving intra-abdominal immunotherapy.
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PMID:Selective induction of PDGF gene expression in peritoneal macrophages by interleukin-2. 808 55

Using a rat model of acute lung inflammation induced by intratracheal instillation of lipopolysaccharide (LPS), we investigated the kinetics of mRNA expression and the potential cellular sources of tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), interleukin (IL)-1 beta, IL-6, RANTES, and transforming growth factor-beta 1 (TGF-beta 1). By Northern blot analysis, TNF-alpha and MIP-2 mRNAs in total lung tissue increased markedly by 30 min and peaked by 1 h after LPS exposure, whereas expression of IL-1 beta and IL-6 was not detected until 1 h and peaked within 6 h. In contrast, neither RANTES nor TGF-beta 1 mRNA was induced by LPS throughout 72 h, although a basal expression was detected in both saline- and LPS-treated lung tissues. At 1 h after LPS, the bronchoalveolar lavage (BAL) fluid contained about 98% alveolar macrophages (AM), whereas by 6 or 12 h, 88% of BAL cells were polymorphonuclear neutrophils (PMN). Upon extraction of total RNA after separation of AM from PMN in BAL, Northern analysis showed that at 1 h, AM expressed pronounced signals for TNF-alpha, MIP-2, IL-1 beta, and IL-6. At 6 and 12 h, however, while cytokine transcripts decreased in AM, PMN exhibited strong signals for these cytokines. A low basal noninducible signal for TGF-beta 1 but not RANTES was detected in both AM and PMN. Finally, by in situ hybridization techniques, PMN in the lung tissue, particularly those located in the vicinity of the bronchiole and vasculature, were demonstrated to localize MIP-2 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. 811 Apr 70


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