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)

Alveolar macrophages (AM) recovered from the lower respiratory tract of individuals with interstitial lung disease (ILD) proliferate at a 2- to 15-fold increased rate (P.B. Bitterman et al. 1984. J. Clin. Invest. 74:460-469). Normal AM stimulated with immune complexes or asbestos release platelet-derived growth factor and insulin-like growth factor-I (IGF-I), and AM activated in vivo in ILD release these growth factors. We evaluated normal unstimulated and activated AM for the receptor for IGF-I to determine if macrophage IGF-I could be involved in the enhanced macrophage proliferation. Although normal AM did not have specific 125I-labeled recombinant IGF-I binding, AM activated by chrysotile asbestos or lipopolysaccharide in vitro or from individuals with ILD had detectable binding that could be inhibited by an anti-IGF-I receptor monoclonal antibody in a dose-dependent fashion. Autoradiography with 125I-labeled recombinant IGF-I revealed binding to the IGF-I receptor on the surface of activated AM, and the percentage of labeled cells was reduced with anti-IGF-I receptor monoclonal antibody or excess unlabeled recombinant IGF-I. Hybridization of total AM RNA to a 32P-labeled IGF-I receptor riboprobe using solution hybridization demonstrated IGF-I receptor mRNA transcripts in AM from an individual with asbestosis, consistent with active expression of the IGF-I receptor gene. In the context of the known role of IGF-I as a growth factor for many cells, these data are consistent with the concept that IGF-I and its receptor may play an important role in the proliferation of AM in the inflamed lower respiratory tract.
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PMID:Activated alveolar macrophages express the insulin-like growth factor-I receptor. 185 Jun 6

In the course of studies of cell-mediated immunity in Graves' disease, we noted that normal peripheral blood monocytes, when stimulated by bacterial lipopolysaccharide, conditioned their media with a factor that had the physicochemical properties of the lymphokine interleukin-1 (IL-1) and that enhanced DNA synthesis and replication in quiescent FRTL5 cells, a line of nontransformed rat thyroid follicular cells. This finding led to the present studies, in which the effect of IL-1 (recombinant IL-1-p) on DNA synthesis in FRTL5 was explored. In the absence of serum, IL-1 induced a small, but significant, increase in [3H]thymidine incorporation into DNA. Calf serum (0.5%) alone also stimulated DNA synthesis slightly, but it greatly enhanced, in a synergistic manner, the stimulatory response to IL-1, decreasing the minimally effective concentration of IL-1 and amplifying the response to higher concentrations. A similar synergism was noted when quiescent FRTL5 were cultured with a combination of IL-1 and a low concentration of insulin-like growth factor-I (IGF-I), which itself stimulated DNA synthesis modestly. IL-1 also increased levels of the mRNA of the proto-oncogene c-myc in quiescent FRTL5, as TSH does, an effect thought to reflect commitment of the cell to increased growth. The findings indicate that IL-1 is an independent stimulator of thyroid cell growth, and that its effects are greatly enhanced by serum, probably in large measure by the IGF-I contained therein. They raise the possibility that IL-1 generated locally by intrathyroid macrophages may act directly by a short-loop mechanism to increase goiter formation in autoimmune thyroid disease.
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PMID:Interleukin-1 stimulates thyroid cell growth and increases the concentration of the c-myc proto-oncogene mRNA in thyroid follicular cells in culture. 349 69

The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insulin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopolysaccharide (LPS)-induced changes in the IGF system. The overnight infusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha decreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IGFBP-1 was increased in plasma, liver, and muscle in response to TNF-alpha. In a second study, rats were injected with LPS after treatment with a neutralizing anti-TNF antibody (Ab), and blood and tissues were collected 4 h later. In LPS-treated rats, plasma concentrations of GH and IGF-I were reduced. LPS also decreased the IGF-I content in liver and skeletal muscle and increased plasma, liver, and muscle concentrations of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induced reduction in IGF-I and the increased IGFBP-1 in plasma and liver and completely prevented the decrease in IGF-I observed in muscle. In contrast, the LPS-induced decrease in plasma GH and the increased IGFBP-1 observed in muscle were unaltered by the anti-TNF Ab.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor. 750 12

The purpose of the present study was to investigate the regulation of plasma and tissue levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1, -2, and -3 (IGFBP-1, -2, and -3) in rats injected with Escherichia coli lipopolysaccharide (LPS), a component of the outer cell wall of gram-negative bacteria. When injected iv into conscious overnight fasted rats, plasma IGF-I levels were initially decreased within 1 h, maximally depressed at 4 h, and still only 35-45% of control values at 24 h. GH levels were reduced as early as 30 min after LPS, averaged 80-90% of control values between 1-4 h, but had returned to basal levels by 24 h. The magnitude and duration of these changes were similar regardless of whether 100 or 10 micrograms/100 g BW (LD20 and LD0, respectively) LPS were injected. Plasma levels of IGFBP-1 and a 28K mol wt BP (BP-28K) were elevated 2- to 3-fold 4 h after LPS treatment, whereas IGFBP-3 and -2 levels were unchanged. The elevation in plasma IGFBP-1 and IGFBP-28K was observed as early as 1 h and was sustained for up to 24 h after LPS treatment. IGF-I levels were decreased 30-50% in liver, pituitary, and skeletal muscle, unchanged in brain, and elevated 5-fold in kidney in response to LPS. Of the tissues sampled, IGFBP-3 and -2 were selectively elevated in liver after LPS treatment. IGFBP-1 was increased in liver, muscle, and kidney in response to LPS. The level of the 28,000 mol wt BP was increased in liver (83%) and not changed in muscle or brain. These data indicate that LPS produces both rapid and sustained alterations in circulating levels of GH, IGF-I, and IGFBPs. Furthermore, there were marked tissue-specific changes in levels of IGF-I and IGFBPs. LPS-induced changes in plasma and tissue IGFBP-3 were not regulated by changes in GH, and changes in insulin could not explain the alterations in IGFBP-1 and -2. These results suggest that after the injection of LPS, changes in IGF-I and IGFBP levels are regulated by a mechanism(s) different from those previously described.
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PMID:Differential tissue regulation of insulin-like growth factor-I content and binding proteins after endotoxin. 751 Oct 91

Spontaneous production of insulin-like growth factor-I (IGF-I) by inflammatory macrophages contributes to aberrant wound healing, but little is known about regulation of IGF-I synthesis in myeloid cells. The T cell-derived cytokine interferon-gamma (IFN gamma) inhibits several fibrogenic and angiogenic components of the wound-healing response. We have used metabolic labeling of primary colony stimulating factor-1 (CSF-1)-derived macrophages and a transformed macrophage cell line (PU5-1R) followed by immunoprecipitation to demonstrate that synthesis of the 17 kilodalton (kDa) prepro-IGF-I protein by these cells is substantially inhibited by IFN gamma. An exon 4 IGF-I/beta-actin riboprobe expression cassette was used in RNase protection assays to show that IFN gamma also reduces steady state levels of IGF-I mRNA in three different populations of macrophages in a time- and dose-dependent manner. This effect is specific for IFN gamma because neither the IFNs-alpha/beta nor lipopolysaccharide (LPS) affects expression of steady state IGF-I transcripts. Down-regulation of IGF-I mRNA by IFN gamma is dependent on de novo protein synthesis and is abrogated by coculture with cycloheximide. Nuclear run-on assays revealed that elongation of IGF-I transcripts is absent in fresh bone marrow cells but is induced several-fold after cells are cultured for 6 days with CSF-1. Treatment of these CSF-1-derived macrophages with IFN gamma for 6 h substantially inhibits synthesis of IGF-I mRNA. Studies on the decay of IGF-I mRNA in PU5-1R macrophages treated with an RNA polymerase inhibitor confirmed that the decline in IGF-I steady state mRNA in IFN gamma-treated cultures arises from an inhibition of transcription rather than from a reduction in mRNA stability. Since a variety of inflammatory mediators can induce expression of IGF-I in macrophages, inhibition of macrophage IGF-I synthesis by IFN gamma provides a mechanism by which leukocytes regulate levels of this growth factor in their microenvironment.
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PMID:Interferon-gamma inhibits macrophage insulin-like growth factor-I synthesis at the transcriptional level. 777 81

To better understand the extrarenal production of active vitamin D metabolites by cells of the monocyte/macrophage lineage, we investigated the 25-hydroxyvitamin D (25OHD)-1-hydroxylation reaction in the v-myc-transformed chick myelomonocytic cell line HD-11; the 1-hydroxylation reaction in this cell line has a high affinity for 25-hydroxylated vitamin D substrates, is localized to mitochondria, and is associated with cytochrome P450 activity. In this study we demonstrated that the HD-11 cell 1-hydroxylation reaction in vitro is not affected by the majority of extracellular regulatory factors that modulate expression of the renal 25OHD-1-hydroxylase in vivo. A 50% increase in extracellular calcium and phosphate concentrations, physiological inhibitory events for renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis, did not decrease basal expression of the HD-11 cell 1-hydroxylation reaction, nor did a 50% decrease in extracellular calcium and phosphate concentrations, stimulatory signals for the 1-hydroxylase in vivo, increase 1,25-(OH)2D3 synthesis in vitro. Receptor-saturating concentrations of PTH and PTH-related peptide were similarly without effect. In contrast, the HD-11 1-hydroxylation reaction was significantly stimulated in a dose-dependent fashion by the macrophage stimulatory agents lipopolysaccharide [P < 0.001 at a maximum effective concentration (EC100) of 25 micrograms/ml] and interferon-gamma (P < 0.001 at EC100 of 1000 IU/ml) and by insulin-like growth factor-I (P < 0.01 at EC100 of 15 nM) with the rank order of stimulation being interferon-gamma > lipopolysaccharide > insulin-like growth factor-I. Dexamethasone (> or = 10 nM) and the cytochrome P450 inhibitors (EC100, 20 microM), ketoconazole, clotrimazole, and menadione, all significantly inhibited the HD-11 cell 1-hydroxylation reaction. The naphthoquinone menadione, which blocks electron transfer to the P450-associated enzyme, was the most effective inhibitor of the reaction in both intact cells (3 +/- 1% of basal expression; P < or = 0.002) and after reconstitution of HD-11 cell mitochondrial extracts with a ferredoxin, reductase, O2, and NADPH (5 +/- 1% of basal; P < or = 0.02). We have also shown that 1,25-(OH)2D3 produced from substrate 25OHD3 appears to exert an endogenous (intracrine) inhibitory effect on HD-11 cell growth; incubation of HD-11 cells with a concentration of ketoconazole (10 microM) known to reduce 1,25-(OH)2D3 production by roughly 50% restored 50% of the growth deficit induced by 1,25-(OH)2D3 (EC100, 100 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulated production and intracrine action of 1,25-dihydroxyvitamin D3 in the chick myelomonocytic cell line HD-11. 819 84

Our previous work has shown that cells of the immune system produce a growth hormone (GH) molecule similar to that secreted by the pituitary. In the present studies, we evaluated the possibility that normal spleen cells producing GH transferred to dwarf mice could stimulate their growth. The results showed that normal spleen cells alone or spleen cells treated with growth-hormone-releasing hormone (GHRH) did not appear to significantly stimulate the growth of dwarf mice. Spleen cells activated in vitro with concanavalin A or lipopolysaccharide and then transferred to dwarf mice, or thymus cells alone, were also without effect, whereas GH alone stimulated growth as expected. Serum levels of insulin-like growth factor-I (IGF-I) and IGF-I-liver RNA were undetectable in control dwarf mice and dwarf mice receiving spleen cells, whereas serum levels of IGF-I increased after treatment of dwarf mice with GH. The immune system of dwarf mice receiving spleen cells, however, was significantly altered. Spleen cells from dwarf animals showed enhanced immunoglobulin, interleukin (IL)-6, IL-2, and interferon-gamma production whereas no significant change was apparent in natural killer cell activity. Despite the absence of the pit-1 protein in dwarf mice, their spleen and thymus cells retained the ability to produce almost as much lymphocyte GH as normal. Overall, the findings support the idea that the pit-1 protein in lymphocytes of dwarf mice may not be obligatory for the expression of lymphocyte GH.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of the administration of growth-hormone-producing lymphocytes on weight gain and immune function in dwarf mice. 852 85

GH has been demonstrated to play a physiological role in the priming of macrophages for tumor necrosis factor-alpha (TNF alpha) synthesis. Although evidence has been presented that GH exerts this effect by an indirect mechanism, the mediators of GH stimulation of TNF alpha synthesis have not been identified. Because insulin-like growth factor-I (IGF-I) is a major mediator of many GH effects, in the present study we investigated the direct in vitro effect of this growth factor on macrophage TNF alpha production. Treatment of murine macrophages with physiological concentrations of IGF-I (0.13-130 nM) enhanced both basal and lipopolysaccharide-stimulated macrophage TNF alpha release and messenger RNA levels. Induction of basal TNF alpha production was also observed after treatment of the cells with supraphysiological concentrations of insulin (130-1300 nM). Exposure of human monocytes to IGF-I led to a similar increase of basal TNF alpha production and messenger RNA expression. Preexposure of macrophages with specific antibodies against IGF-I and IGF-I receptor before IGF-I addition resulted in a complete abrogation of the stimulatory effect of IGF-I on TNF alpha production, indicating that specific binding of IGF-I to its receptor is required for macrophage TNF alpha induction by IGF-I. In contrast to the stimulatory effect of IGF-I, neither GH (0.1-10 micrograms/ml) nor IGF-II (0.13-130 nM) enhanced macrophage TNF alpha release in vitro. To assess the role of the tyrosine kinase system in mediating IGF-I-induced basal TNF alpha production, macrophages were preincubated with the specific tyrosine kinase inhibitors, genistein and tyrphostin A9, before IGF-I exposure. Addition of these compounds resulted in a dose-dependent inhibition of the stimulatory effect of IGF-I on macrophage TNF alpha release, indicating that protein tyrosine kinase activation is required for TNF alpha stimulation by IGF-I. Taken together, these results demonstrate that IGF-I is a monocyte/macrophage activating factor that enhances TNF alpha production, and that such effect is mediated via the IGF-I receptor and involves tyrosine kinase activation.
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PMID:Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-alpha production. 889 24

The classical distinction between hormones and cytokines has become increasingly obscure with the realization that homeostatic responses to infection involve coordinated changes in both the neuroendocrine and immune systems. The hypothesis that these systems communicate with one another is supported by the ever-accruing demonstrations of a shared molecular network of ligands and receptors. For instance, leukocytes express receptors for hormones and these receptors modulate diverse biological activities such as the growth, differentiation and effector functions. Leukocyte lineages also synthesize and secrete hormones, such as insulin-like growth factor-I (IGF-I), in response to both growth hormone (GH) and also to cytokines such as tumor necrosis factor-alpha (TNF-alpha). Since hormones share intracellular signaling substrates and biological activities with classical lymphohemopoietic cytokines, neuroendocrine and immune tissues share a common molecular language. The physiological significance of this shared molecular framework is that these homeostatic systems can intercommunicate. One important example of this interaction is the mechanism by which bacterial lipopolysaccharide, by eliciting a pro-inflammatory cytokine cascade from activated leukocytes, modulate pituitary GH secretion as well as other CNS-controlled behavioral and metabolic events. This article reviews the cellular and molecular basis for this communication system and proposes novel mechanisms by which neuroendocrine-immune interactions converge to modulate disease resistance, metabolism and growth.
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PMID:Hormones, lymphohemopoietic cytokines and the neuroimmune axis. 910 83

Endothelin-1 (ET-1) mRNA expression and protein production were examined in primary rat articular chondrocyte (AC) cultures by RT-PCR and radioimmunoassay, respectively. We found that serum-starved rat AC express ET-1 mRNA and produce the peptide constitutively. Treatment of cells with 10% FCS resulted in a marked increase in ET-1 levels with a peak at 48 h (5.6-fold). A similar concentration-dependent effect was also obtained in the presence of interleukin 1beta (3.1-fold), tumour necrosis factor alpha (3. 5-fold), lipopolysaccharide (2.7-fold), transforming growth factor beta1 (3.5-fold), epidermal growth factor (5.0-fold) and insulin-like growth factor-I (4.4-fold). In addition, ET-1 was found to induce, over a period of 24 h, a potent concentration-dependent stimulation of DNA synthesis in rat AC. These findings demonstrate for the first time the constitutive expression and production of ET-1 by rat AC which could be modulated by several cytokines and growth factors, suggesting a possible role for ET-1 in autocrine regulation of chondrocyte function.
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PMID:Constitutive and inducible expression of endothelin-1 in primary rat articular chondrocyte culture. 924 82


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