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

Interleukin 6 (IL-6) probably plays a central role in the acute phase response and in haemopoiesis and may be involved in the control of bone turnover. We have studied the release of IL-6 from human trabecular bone cells treated with a variety of stimuli using a specific bioassay. In serum free medium, unstimulated human osteoblast-like cells produced IL-6 in the range of 1000-2050 pg/ml/24 h. Recombinant human interleukin 1 (IL-1 alpha) (10(-13)-10(-11) M), tumor necrosis factor alpha (TNF alpha) (10(-9)-10(-7) M) and lipopolysaccharide (5-500 ng/ml) all stimulated release of IL-6 from human bone cells. Maximal levels of 17,000 pg/ml were observed using the highest concentration of IL-1. 1,25(OH)2D3 and PTH did not stimulate IL-6 release. Using a specific sheep antihuman IL-6 antibody, all IL-6 activity could be neutralized. In parallel studies, ROS 17/2.8 rat osteosarcoma cells released around 50 pg/ml of IL-6 under basal conditions which were increased to a maximum of 900 pg/ml by treatment with PTH (10(-9) M). The cytokines were less effective and 1,25(OH)2D3 again had no effect. Modulation of expression of IL-6 mRNA in human osteoblast cells was examined using a human complementary deoxyribonucleic acid probe. The mRNA was constitutively expressed, and IL-1 (10(-11) M) and TNF (10(-7) M) induced further mRNA expression within 2 h, which was sustained over 24 h. 1,25(OH)2D3 (10(-7) M), IL-6 (2000 pg/ml), and PTH (10(-9) M) exerted no effects at any time point. Dexamethasone (10(-6) M) suppressed both basal and IL-1- and TNF-induced IL-6 mRNA expression. IL-6 receptor mRNA was constitutively expressed but was not regulated by any of the above agents. It is clear that rodent and human osteoblasts differ in their production of IL-6 and its modulation. These data support the hypothesis that IL-6 is produced locally in human bone by osteoblasts under the direction of other cytokines. This could have implications in bone remodeling, haemopoiesis, and systemic responses to local injury.
 ...
PMID:The modulation of the expression of IL-6 and its receptor in human osteoblasts in vitro. 171 33

Substance P (SP) is an undecapeptide with neurotransmitter and immunoregulatory properties. In murine schistosomiasis, ova naturally induce liver and intestinal granulomas. These granulomas contain macrophages, and eosinophils that produce SP. A report showed that human blood monocytes isolated by adherence release interleukin-1 (IL-1) in response to SP (Lotz et al. (1989) Science 241, 1218). IL-1 is important for initiation of hypersensitivity granulomas. Therefore, it was determined whether SP modulates granuloma macrophage IL-1 production in murine schistosomiasis. Macrophages were obtained from lung and liver granulomas, and from spleens of infected mice. A thymocyte proliferation assay measured IL-1 activity in culture supernatants. Total RNA, extracted from macrophages, was assayed for IL-1 alpha and beta mRNA by Northern blotting using cDNA probes. In response to lipopolysaccharide (LPS), splenic macrophages and macrophages from young lung granulomas released appreciable IL-1. Macrophages from liver granulomas, that were lesions older than the lung granulomas, were unresponsive to LPS with regard to IL-1 secretion. Yet, granuloma macrophages spontaneously expressed IL-1 alpha and beta mRNA. LPS enhanced IL-1 mRNA expression in both splenic and granuloma macrophages. Exposure of macrophages from all sources to SP did not alter IL-1 secretion or gene expression. Similarly, the responsiveness of macrophages to LPS was not affected by concomitant exposure to SP. It is concluded that, in the murine system, SP does not directly influence splenic or granuloma macrophage IL-1 secretion or gene expression. Also, it appears that macrophage secretion of IL-1 is rapidly down-regulated following granuloma elicitation.
 ...
PMID:Substance P does not alter interleukin-1 expression by splenic or granuloma macrophages in murine schistosomiasis. 171 19

The capacity of human monocytes/macrophages (M/M) infected with a human immunodeficiency virus-1 (HIV-1) isolate to produce several immunomodulating cytokines including interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-8, and macrophage chemoattractant and activating factor (MCAF) was examined. Although HIV infection itself induced significant increases in the level of mRNAs for IL-1 beta, TNF-alpha, IL-6, and IL-8, the levels of lipopolysaccharide (LPS)-induced mRNAs for IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, IL-8, and MCAF were decreased over those of uninfected LPS-stimulated cells. In addition, HIV-infected M/M produced lower amounts of IL-8 protein, as measured by radioimmunoassay over an 18-day culture period. These results suggest that HIV infection generally suppresses the LPS-inducible cytokine production in human M/M. The impact of the role of these cytokines in the immunity and pathogenesis of HIV-1 infection is discussed.
 ...
PMID:Decrease in cytokine production by HIV-infected macrophages in response to LPS-mediated activation. 172 30

We recently reported an abnormal production of interleukin-1 (IL-1) in peripheral macrophages of several neurological mutant mice that exhibit patterns of neuronal degeneration, especially in the cerebellum. After in vitro activation by lipopolysaccharide acid (LPS), these macrophages hyperexpress IL-1 beta mRNA and hyperproduce IL-1 protein in comparison with +/+ controls. In the present study, focused on the staggerer mutant mice, we investigate if this genetic dysregulation is specific for IL-1 beta or if it reflects a generalized hyperexcitability of these macrophages. The hyperexpression of IL-1 beta mRNA in sg/sg macrophages is present whatever the duration of LPS stimulation, even for periods as short as 15 min, although it reaches a maximum after 4 h of stimulation. The hyperinducibility of sg/sg macrophages is observed even when very low doses of LPS are used (0.01 microgram/ml) and reaches its maximum for 5 micrograms/ml LPS. Synthetic molecules (muramyl dipeptides), such as N-acetylmuramyl-L-alanyl-D-isoglutamine or murabutide, known as macrophage activators, are also efficient in revealing the cytokine hyperexpression in sg/sg macrophages. In addition, hyperexpression of two other cytokines, i.e., tumor necrosis factor-alpha and IL-1 alpha mRNAs, is also detected in LPS-stimulated macrophages of mutant mice. Finally, the effect of an inhibitor of protein synthesis, cycloheximide, is similar in +/+ and sg/sg macrophages. As a whole, these data lead us to conclude that the sg/sg macrophages are in a state of general hyperexcitability when compared with +/+ ones.
 ...
PMID:Evidence for a hyperexcitability state of staggerer mutant mice macrophages. 172 30

Oncogene-transformed BALB/c-3T3 fibroblasts which spontaneously or upon immune-activation with cytokines and lipopolysaccharide (LPS) generate IL-1 alpha, were tested for their tumorigenicity as well as their interaction with natural immune defense by NK cells and macrophages. Oncogene-transformed fibroblasts were weakly tumorigenic, since not all mice developed tumors despite application of high doses of tumor cells. This was independent of the immune status of the host. However, in the immunocompetent host those transformed fibroblast lines which spontaneously produced IL-1 alpha grew only transiently and then regressed. After induction of IL-1 alpha production, a decrease in the rate of tumor take was noted and the rate of regression of developing tumors was increased. Regression of IL-1-producing transformed fibroblasts was strongly reduced but not completely abolished in sublethally irradiated mice. This indicated that IL-1 production may predominantly influence T-cell-mediated defense, but some influence on non-adaptive immunity could not be excluded a priori. IL-1 production did not influence susceptibility of transformed fibroblasts towards NK cells and macrophages. However, IL-1-producing transformed fibroblasts were most potent stimulators of NK cells and macrophages, the stimulatory effect being locally restricted. In conclusion, IL-1 producing, oncogene-transformed fibroblasts which generated the cytokine constitutively or upon immune-activation, were rejected from the tumor-bearing host following initial growth. Fibroblast-induced local activation of NK cells and macrophages was shown to play some role in tumor graft rejection. The influence of IL-1 production of transformed fibroblasts on T-cell-mediated defense is addressed in the accompanying report.
 ...
PMID:Interleukin-1 produced by tumorigenic fibroblasts influences tumor rejection. 173 13

The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterizes early atherogenesis. Macrophages are also present in more advanced human atherosclerotic plaques and can produce many mediators that may contribute to lesion formation and progression. Macrophage colony-stimulating factor (MCSF) enhances the proliferation and differentiation of monocyte progenitors and is required for the survival and activation of mature monocytes and macrophages. The authors therefore examined the expression of the MCSF gene in cultured human vascular endothelial (EC) and smooth muscle cells (SMC) as well as in atheromatous lesions from rabbits and humans. Growth arrested EC and SMC contain a low level of MCSF mRNA. Bacterial lipopolysaccharide (LPS), recombinant human interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor alpha (TNF alpha) induced MCSF mRNA accumulation in a concentration-dependent manner in both EC and SMC. These stimuli induced large increases in MCSF mRNA with peak induction between 4-8 hours after treatment. LPS, IL-1 alpha, and TNF alpha stimulated EC and SMC also showed increased fluorescent antibody staining for MCSF protein and released immunoreactive MCSF in a time-dependent manner. In contrast, phorbol 12-myristate 13-acetate (PMA) was a less potent inducer of MCSF gene expression and iron-oxidized low-density lipoproteins (ox-LDL) did not increase consistently MCSF mRNA or the synthesis and secretion of immunoreactive protein. Northern analysis of mRNA isolated from the atheromatous aorta of rabbits fed a 1% cholesterol diet for 10 weeks showed elevated MCSF mRNA compared with controls. Immunostaining of atheromatous arterial lesions of rabbits demonstrated MCSF protein in association with intimal SMC as well as macrophages. Furthermore, polymerase chain reaction (PCR) analysis of MCSF mRNA in human atheromata showed higher levels than found in nonatherosclerotic arteries and veins. Since the authors found no mRNA for the MCSF receptor, c-fms, in cultured EC or SMC macrophages are likely the primary target for MCSF within atheromatous vessels. The authors therefore investigated the effects of MCSF on monocyte functions related to foam cell development. Treatment of cultured human monocytes with recombinant human MCSF (10(3) U/ml, 72 hr) led to the accumulation of mRNA for the acetyl-LDL (scavenger) receptor and apolipoprotein E (apo E). These studies establish that vascular EC and SMC produce substantial MCSF in response to a variety of stimuli. The local production of MCSF during atherogenesis may contribute to macrophage survival and proliferation or activate specific macrophage functions such as expression of the scavenger receptor and secretion of apo E.
 ...
PMID:Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. 173 24

Antibiotics do not act alone but act in conjunction with the host defense system. In particular, it has been shown that some antibiotics can modify cytokine production. We compared the in vitro effects of three macrolides (roxithromycin, spiramycin, and erythromycin) actively concentrated by leukocytes on interleukin-1 alpha, (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha production by human monocytes stimulated with lipopolysaccharide. Our results show that the three macrolides tested have different effects on production of these cytokines. Spiramycin and, to a lesser extent, erythromycin increased total IL-6 production without affecting IL-1 alpha, IL-1 beta, or tumor necrosis factor alpha production, whereas roxithromycin had no effect. To our knowledge, this is the first time that an antibiotic has been shown to increase IL-6 production.
 ...
PMID:Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin. 175 22

The expression of mRNA coding for IL-1 alpha and IL-1 beta was examined in human peripheral blood monocytes (PBM) to determine if the two genes are under the same mechanisms of transcriptional control and whether or not they can be regulated independently. In response to E. coli lipopolysaccharide (LPS), PBM express approximately 10-fold more IL-1 beta-specific mRNA than IL-1 alpha. However, treatment of these cells with phorbol myristate acetate (PMA) resulted in the expression of IL-1 beta mRNA. Likewise, treatment of PBM with phorbol dibutyrate (PdBu), phorbol diacetate (PDA), or mezerein, which, similar to PMA, were able to induce the translocation of protein kinase C (PKc) to the monocyte plasma membrane, resulted in predominantly IL-1 beta mRNA expression. The inactive tumor promoter 4 alpha-phorbol didecanoate (4 alpha-PDD) did not cause the translocation of PKc or induce the expression of either form of IL-1 mRNA. Following 18 h pretreatment with PMA to downregulate PKc activity, LPS was capable of inducing the expression of both forms of IL-1 mRNA, demonstrating that at least part of the response of PBM to LPS is PKc independent. These results suggest that the activation of PKc alone is sufficient to induce a high level expression of IL-1 beta but not IL-1 alpha mRNA. Furthermore, the possibility exists that another, as yet unknown, signal transduction mechanism is involved in inducing the expression of both IL-1 alpha and IL-1 beta mRNA in response to LPS.
 ...
PMID:Differential regulation of interleukin-1 alpha and interleukin-1 beta mRNA expression in human monocytes: evidence for protein kinase C-dependent and -independent pathways. 176 43

The possible involvement of interleukin-1 alpha (IL-1 alpha) in the pathogenesis of murine hepatitis model induced with galactosamine and lipopolysaccharide (LPS) was investigated. The injection of 10 ng/mouse of LPS in combination with 10 mg/mouse of galactosamine into mice induced hepatic damage at 24 hours. Treatment with anti-mouse IL-1 alpha antiserum 30 min before galactosamine/LPS injection showed a tendency to reduce the liver injury, while pretreatment with anti-mouse tumor necrosis factor-alpha (TNF) antiserum significantly protected mice from liver injury. The use of recombinant murine TNF, instead of LPS, in combination with galactosamine could elicit hepatic damage, whereas recombinant murine IL-1 alpha could not substitute for LPS. However, recombinant murine IL-1 alpha enhanced the hepatotoxic effect of recombinant murine TNF in galactosamine-sensitized mice. These results suggest that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-1 alpha acts synergistically with TNF in this hepatitis model.
 ...
PMID:Interleukin-1 alpha enhances hepatotoxicity of tumor necrosis factor-alpha in galactosamine-sensitized mice. 177 33

Recent studies have demonstrated the expression of messenger RNA (mRNA) for several cytokines within atherosclerotic arteries. Since cytokines have been shown to modulate functions of cultured arterial wall cells in a manner that could influence atherogenesis, this suggests that factors that modulate cytokine production would influence the atherosclerotic process. To examine whether lipoproteins can modulate cytokine production, the effect of lipoproteins on mouse macrophage interleukin-1 beta (IL-1 beta) mRNA expression was examined by dot blot and Northern blot analyses. Low density lipoprotein (LDL), acetylated-LDL, or malondialdehyde-LDL did not induce IL-1 beta mRNA expression or affect the expression in response to lipopolysaccharide (LPS). Similarly, copper ion-oxidized LDL did not stimulate the production of IL-1 beta mRNA. However, oxidized LDL inhibited the LPS-induced expression in a concentration- and time-dependent manner with a maximum inhibition (greater than 90%) observed after a 2.5 h preincubation with 25 micrograms protein/ml. These conditions did not affect protein synthesis or phagocytosis and the inhibition was partially reversible after 24 h, which together suggest that the inhibition was not due to cell death. An inhibition of IL-1 alpha and IL-6 mRNA expression was also observed while there was no change in gamma-actin mRNA levels. The level of inhibition of IL-1 beta mRNA was dependent upon the extent of LDL oxidation, but did not correlate with recognition by the scavenger receptor. A non-receptor pathway was supported by two lines of evidence: 1) the inhibition could be reproduced with a lipid extract, and 2) oxidized LDL also inhibited scavenger receptor negative THP-1 cell IL-1 beta mRNA expression. Finally, oxidized LDL had no effect on the turnover of IL-1 beta mRNA, suggesting that the decreased accumulation of IL-1 beta mRNA is due to a decrease in gene transcription. Together these studies suggest that as macrophages become foam cells their immune responsiveness is attenuated.
 ...
PMID:Inhibition of lipopolysaccharide-induced interleukin-1 beta mRNA expression in mouse macrophages by oxidized low density lipoprotein. 181 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>