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)

The signaling mechanisms responsible for the induced expression of interferon (IFN) genes by viral infection or double-stranded RNA (dsRNA) are not well understood. Here we investigate the role of the interferon-induced dsRNA-dependent protein kinase PKR in the regulation of IFN induction. Biological activities attributed to PKR include regulating protein synthesis, mediating IFN actions, and functioning as a possible tumor suppressor. Since binding of dsRNA is required for its activation, PKR has been considered as a candidate signal transducer for regulating IFN expression. To examine this role of PKR, loss-of-function phenotypes in stable transformants of promonocytic U-937 cells were achieved by two different strategies, overexpression of an antisense PKR transcript or a dominant negative PKR mutant gene. Both types of PKR-deficient cells were more permissive for viral replication than the control U-937 cells. As the result of PKR loss, they also showed impaired induction of IFN-alpha and IFN-beta genes in response to several inducers--specifically, encephalomyocarditis virus, lipopolysaccharide, and phorbol 12-myristate 13-acetate. Interestingly, while IFN-alpha induction by dsRNA was impaired in PKR-deficient cells, IFN-beta induction remained intact. Loss of PKR function also resulted in decreased antiviral activity as elicited by IFN-alpha and, to a greater extent, by IFN-gamma. These results implicate PKR in the regulation of several antiviral activities.
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PMID:Involvement of the double-stranded-RNA-dependent kinase PKR in interferon expression and interferon-mediated antiviral activity. 756 28

Infection of injury results in several systemic and central reactions termed the acute phase response (APR). Substantial evidence suggests that cytokines induced by microbes initiate the APR. We compared the APR induced in rabbits by a model bacterial stimulus, lipopolysaccharide (LPS), to that induced by a model viral stimulus, polyriboinosinic:polyribocytidylic acid (poly I:C). The cytokine mRNA responses in a mouse macrophage cell line (RAW 264.7) to LPS or poly I:C were also determined. Rabbits were injected intravenously or intracerebroventricularly with different doses of LPS or poly I:C. Colonic temperatures (Tco) and blood samples were taken at the time of injection and at 3, 6, and 24 h after injection. Leukocyte numbers, serum antiviral activity, serum ceruloplasmin, and plasma fibrinogen were analyzed. Both intravenously injected LPS and poly I:C increased Tco, decreased leukocytes, and increased ceruloplasmin. Only LPS by the intravenous route increased fibrinogen, whereas only intravenously injected poly I:C induced antiviral activity. Intracerebroventricular injections of LPS and poly I:C also elicited dose-dependent febrile responses but did not change the hematologic APR significantly except for fibrinogen. The primary distinctions between LPS and poly I:C with respect to cytokine induction in the RAW 264.7 macrophage cell line were that LPS failed to induce interferon (IFN)-alpha, poly I:C induced interleukin (IL)-6 mRNA minimally and for a shorter time period than did LPS, and LPS induced IL-1 alpha and IFN-beta more rapidly than did poly I:C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of acute phase responses induced in rabbits by lipopolysaccharide and double-stranded RNA. 781 Jul 70

The human monocytic cell line THP-1 was used as a model to study the mechanism of infection in the monocyte/macrophage, a natural target of lymphocytic choriomeningitis virus (LCMV) infection in vivo. Both the virulent strain, LCMV.WE, and the avirulent strain, LCMV.ARM, infected THP-1 cells, but did not stimulate THP-1 cells to secrete interleukin 1 (IL-1) or tumour necrosis factor (TNF-alpha). When lipopolysaccharide (LPS) was added to THP-1 cells together with LCMV, an 80 to 90% reduction in the number of infected cells (measured by immunofluorescence) and a 90% reduction in viral plaques was observed 5 to 6 days post-infection. Neither interferon alpha (IFN-alpha) nor IFN-beta were detected in supernatants from THP-1 cells after the addition of LCMV, LPS, or LPS plus LCMV. In contrast, the same levels of IL-1 and TNF-alpha were observed in the presence of LPS and LCMV, or LPS alone. However, antibodies to IL-1, TNF-alpha, interleukin 6 and IFN-alpha did not block the antiviral effect of LPS. In kinetic studies, LPS added 1 day after adding LCMV to THP-1 cells was still effective in reducing the number of infected cells. Our findings suggest that LPS alters cellular metabolism, possibly through the induction of IFN-alpha, and that IFN-alpha in the absence of LPS suppresses virus production.
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PMID:Lipopolysaccharide inhibits the production of lymphocytic choriomeningitis virus in a human monocytic cell line. 834 56

Murine macrophages (M phi) are activated either by interferon-gamma (IFN-gamma) or interferon-alpha/beta (IFN-alpha/beta) in combination with bacterial lipopolysaccharide (LPS) to induce synthesis of tumor necrosis factor alpha (TNF-alpha) and nitric oxide synthase (iNOS) mRNA synthesis for generation of tumor cytotoxic nitric oxide (NO). In the present study, the effect of exogenous IFN-gamma on the induction of endogenous mRNA synthesis and secretion of IFN-alpha/beta by murine M phi was investigated. Neutralizing antibodies to IFN-alpha/beta reversed TNF-alpha and NOS mRNA synthesis, as well as nitric oxide (NO)-mediated tumor cytotoxicity. Quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that treatment of M phi with IFN-gamma induced increases in both IFN-alpha and IFN-beta mRNA synthesis by approximately 2-fold and 10-fold, respectively, which corresponded to a 2-fold increase in secretion of IFN-alpha/beta by ELISA. These data indicate that exogenous IFN-gamma induces endogenous synthesis and secretion of IFN-alpha/beta by M phi, which appears to act in concert with endogenously synthesized TNF-alpha for the autocrine induction of NOS mRNA synthesis.
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PMID:Exogenous interferon-gamma induces endogenous synthesis of interferon-alpha and -beta by murine macrophages for induction of nitric oxide synthase. 856 12

Production of T helper 1 and T helper 2 cytokines was investigated in peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients by a newly described technique, detection of intracellular cytokines by flow cytometry in conjunction with immunophenotype analysis. T-cell gamma interferon (IFN-gamma) production and interleukin 10 (IL-10) production were examined after PBMC activation with T-cell mitogens at 5 and 24 h, and monocyte spontaneous production of IL-10 and production after PBMC activation with lipopolysaccharide (LPS) for 24 h were also examined. The data indicate that MS patients have decreased percentages of T cells capable of secreting IFN-gama compared with healthy controls, and this change is detectable at 5 and 24 h. the patients displaying decreased T-cell production of IFN-gamma were essentially confined to a group being treated with the newly approved drug Betaseron (berlex Labs, Cedar Knolls, N.J.), a recombinant form of IFN-beta (rIFN-beta 1b). By gating of the entire lymphocyte population, analysis of IFN-gama production in T cells (CD3+ versus that in non-T cells (CD3+) was possible. The percentage of IFN-gamma-producing lymphocytes that was made up of T cells was essentially unchanged between the Betaseron-treated patients, non-Betaseron-treated patients, and controls, indicating that the suppression of IFN-gamma production displayed by betaseron-treated MS patients was a nonspecific suppression of all IFN-gamma-producing lymphocytes as opposed to a suppression of T-cell production only. The data seem to indicate that treatment of MS with Betaseron corresponds to an inhibition of the lymphocyte's ability to produce IFN-gamma. No changes were detected in T-cell production of IL-10 at either time point. We also observed that MS patients in general appear to have small percentages of peripheral blood monocytes spontaneously producing slight but detectable levels of IL-10. No difference was seen regarding monocyte production of IL-10 after PBMC activation with LPS between MS patients and controls. Both populations responded with high percentages of monocytes producing IL-10. The data seem to indicate that treatment of MS with Betaseron, known to decrease the exacerbation rate of relapsing-remitting MS, corresponds to a suppression of peripheral blood lymphocyte production of IFN-gamma. Monocyte production of IL-10 may also play a role in regulating the disease process.
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PMID:Detection of altered T helper 1 and T helper 2 cytokine production by peripheral blood mononuclear cells in patients with multiple sclerosis utilizing intracellular cytokine detection by flow cytometry and surface marker analysis. 880 5

Interferon (IFN)-alpha/beta-mediated negative regulation of interleukin 12 (IL-12) and IFN-gamma proteins is reported here. Both IFN-alpha and IFN-beta inhibited fixed Staphylococcus aureus Cowan strain induction of IL-12 and IFN-gamma production by mouse splenic leukocytes in culture. Extended studies with IFN-alpha demonstrated that inhibition was at the level of biologically active IL-12 p70. Effects were selective, as induction of tumor necrosis factor was unaffected and induction of IL-6 was enhanced. Neutralization of IFN-alpha/beta expressed endogenously during infections with murine cytomegalovirus (MCMV) enhanced early IL-12 and IFN-gamma protein production. Furthermore, during infections of mice with lymphocytic choriomeningitis virus (LCMV), this treatment revealed a previously undetected early IL-12 and IFN-gamma protein expression, and mice deficient in IFN-alpha/beta receptor function, but not control mice, also expressed endogenous LCMV-induced IL-12. The effects of IFN-alpha/beta neutralization on production of IL-12 and IFN-gamma during the viral infections were detected in both serum samples and medium conditioned with splenic leukocytes isolated from infected animals. In vitro studies demonstrated that splenic leukocytes isolated from LCMV-infected mice were primed to produce IL-12 in response to stimulation with Staphylococcus aureus Cowan strain, but that this responsiveness was sensitive to added IFN-alpha. Moreover, endogenous IFN-alpha/beta induced by LCMV inhibited in vivo lipopolysaccharide stimulation of IL-12 production. These results demonstrate a new pathway for regulating cytokine responses, and suggest a mechanism for inhibition of IL-12-dependent immune responses during viral infections.
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PMID:Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. 901 36

Numerous cytokines induce symptoms characteristic of the flu syndrome common to acute viral infections. To better characterize the cytokine mRNA profile associated with the early phase of this syndrome, we examined the induction of cytokine mRNAs in spleens of mice 1, 2, and 4 h following intraperitoneal inoculation of Newcastle disease virus (NDV). The reverse transcriptase-polymerase chain reaction was used to detect mRNAs for mouse proinflammatory cytokines [interleukin (IL)-1 alpha, IL-1 beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF), and interferon (IFN)-gamma] and type I IFNs (IFN-alpha 4 and IFN-beta). We observed a rapid (within 2 h) induction of most of these cytokine mRNAs in the mouse spleen following challenge with live NDV or the viral stimulant poly[rI:rC]. IL-1 beta, M-CSF, and IFN-gamma mRNAs were also induced by heat-inactivated NDV, suggesting the possibility of endotoxin contamination of the virus (confirmed by Limulus lysate assay). Examination of cytokine induction by comparable doses of lipopolysaccharide indicated that endotoxin contamination could account for the cytokine mRNA-inducing activity of the heat-inactivated virus. These studies point to a critical control (heat-inactivated virus) for viral cytokine studies. In addition, they indicate that certain cytokine mRNAs (IL-1 alpha, IL-6, M-CSF, IFN-gamma, IFN-alpha, and IFN-beta) are rapidly induced in the spleen when live virus is inoculated intraperitoneally, independently of contaminating endotoxin.
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PMID:Early induction of proinflammatory cytokine and type I interferon mRNAs following Newcastle disease virus, poly [rI:rC], or low-dose LPS challenge of the mouse. 914 48

Previous studies have shown that interleukin-1 (IL-1) enhances interferon (IFN)-gamma-induced indoleamine 2,3-dioxygenase (IDO) enzymatic activity in human monocyte-derived macrophages by increasing expression of IDO mRNA. The objectives of this study were to see if IL-1 also enhances IFN-beta-induced IDO activity by increasing specific mRNA expression and to determine if lipopolysaccharide (LPS) enhances IFN-induced IDO activity in a similar manner. Macrophages were treated with combinations of IFN-beta or IFN-gamma as inducer and LPS or IL-1 as potentiator. After 48 h, IDO mRNA expression was assessed by RT-PCR, and IDO activity was determined by HPLC. LPS alone induced IDO mRNA expression and also increased IDO mRNA expression induced by either type of IFN. Furthermore, IL-1 enhanced IFN-beta-induced IDO mRNA expression. When IDO mRNA was assessed 6 h after treatment, mRNA was detected at concentrations of IFNs or potentiator or both in which enzymatic activity at 48 h was undetectable. Thus, although the mechanism of potentiation of IFN-induced IDO by LPS and by IL-1 involves increased expression of IDO mRNA, it appears that temporal differences in IDO mRNA expression are also important.
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PMID:Potentiation of interferon-induced indoleamine 2,3-dioxygenase mRNA in human mononuclear phagocytes by lipopolysaccharide and interleukin-1. 924 70

Bovine retinal pigmented epithelial (RPE) cells express an inducible nitric oxide synthase (NOS-2) after activation with interferon (IFN)-gamma and lipopolysaccharide (LPS). Experiments were performed to investigate the effects of IFN-alpha and IFN-beta on NOS-2 activity. These types of interferons did not aid LPS in the production of nitrite, but markedly inhibited in a concentration-dependent manner the nitrite release due to LPS/IFN-gamma. Analysis by Western and Northern blots showed that RPE cells co-stimulated with IFN-alpha or IFN-beta with LPS/IFN-gamma accumulated lower levels of NOS-2 protein and mRNA than in the presence of LPS/IFN-gamma alone. The presence of IFN-alpha or IFN-beta did not accelerate mRNA degradation, implying that these interferons did not affect NOS-2 mRNA stability, but more probably NOS-2 gene expression. Furthermore, IFN-gamma binding studies demonstrated that the inhibitory effect of IFN-alpha and IFN-beta is not caused by a blocking of IFN-gamma receptors. Analysis of NF-kappaB activation by electrophoretic mobility shift assay demonstrated that LPS/IFN-gamma-induced NF-kappaB binding was not changed by the presence of IFN-alpha. However, similar experiments revealed that the activation of interferon regulatory factor-1 (IRF-1) by LPS/IFN-gamma was decreased by IFN-alpha. This phenomenon could be due to the decline of IRF-1 mRNA and the up-regulation of IRF-2 mRNA, an IRF-1 repressor, by IFN-alpha. These results suggest that the inhibitory effect of IFN-alpha and -beta on NOS-2 induction could be partially explained by their effect on the induction of the IRFs, which were involved in NOS-2 gene transcription.
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PMID:Inhibition of inducible nitric oxide synthase expression by interferons alpha and beta in bovine retinal pigmented epithelial cells. 940 17

In addition to leukocytes and fibroblasts, the classic sources of human interferons (IFN), many other human cells are now known to be capable of producing IFN. Keratinocytes (KC) are abundant in the skin and provide the first line of defense against viruses and other noxious agents. Human KC are a potent source of cytokines and were implicated as forming IFN-like protein(s). We have investigated whether KC form IFN. We found that culture supernatants from unstimulated human KC did not contain detectable amounts of IFN-alpha or IFN-beta. However, those from KC activated with the potent IFN inducer, polyriboinosinic:polriboycytidylic acid (poly rI:rC), had appreciable antiviral activity, which studies with neutralizing sera showed to be caused by IFN-beta. In ELISA tests, we detected IFN-beta protein in the supernatants but not IFN-alpha protein. Nevertheless, reverse transcription PCR showed that both IFN-alpha and IFN-beta mRNA were upregulated in poly rI:rC-treated KC. The levels of these mRNA were also increased in KC exposed to ultraviolet B (UVB) irradiation, interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha), or lipopolysaccharide (LPS). These results show that IFN-beta is among the cytokines secreted from human KC and, together with IFN-alpha, may have a role in host defense mechanisms in the skin.
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PMID:The expression and modulation of IFN-alpha and IFN-beta in human keratinocytes. 945 59


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