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)

Soluble type II interleukin 1 receptor (IL-1r II) and interleukin 1 receptor antagonist (IL-1ra) regulate inflammation by competitively inhibiting the binding of IL-1 beta to the signalling IL-1 receptor. In addition, glucocorticoids also regulate IL-1 beta by suppressing gene transcription. More recently, glucocorticoids have been shown to increase soluble IL-1r II concentrations, which may contribute to their anti-inflammatory properties. Interestingly, increased serum levels of soluble IL-1r II and IL-1ra have been measured in septic patients, although the mechanism is unclear. In this respect, the authors characterize new pathways in which IL-1r II and IL-1ra may be regulated in sepsis through combined stimulation with lipopolysaccharide (LPS) and dexamethasone of peripheral blood mononuclear cells (PBMC). This paper confirms that while dexamethasone induces release of IL-1r II, LPS augments dexamethasone-induced IL-1r II release 45-fold. Furthermore, LPS plus dexamethasone induces IL-1r II protein and mRNA, whereas LPS alone does not. Additionally, it was shown by flow cytometric analysis that the monocyte is the primary IL-1r II producer in response to LPS and dexamethasone administration. Therefore, LPS and dexamethasone synergism in IL-1r II induction may be important in controlling IL-1 beta effects. In contrast, LPS alone induces IL-1ra, while dexamethasone attenuates this LPS-induced response. Although IL-1r II and IL-1ra may work together to suppress IL-1 beta effects in sepsis, inflammatory cells differentially regulate these cytokines.
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PMID:The combination of endotoxin and dexamethasone induces type II interleukin 1 receptor (IL-1r II) in monocytes: a comparison to interleukin 1 beta (IL-1 beta) and interleukin 1 receptor antagonist (IL-1ra). 904 79

The natural interleukin 1 receptor antagonist (IL-1ra) is induced in mouse liver after lipopolysaccharide (LPS) or recombinant interleukin 1 (IL-1) administration. Changes in hepatic IL-1ra mRNA concentration were measured following LPS injection to CBA mice. The results showed, that in vivo, IL-1ra transcripts were stimulated early at about 2h with maximal elevation at 4-6 h. Northern blot analysis of RNA extracted from primary cultures of mouse hepatocytes did not detect IL-1ra mRNA, although constitutive and stimulated contrapsin mRNA expression were easily demonstrated. Therefore, induction of IL-1ra mRNA in sinusoid lining cells of the mouse liver at 4 h after LPS injection was evidenced by in situ hybridization using the same specific cDNA probe as in the Northern blotting technique. Additionally, immunohistochemical studies revealed that IL-1 receptor antagonist protein was induced with LPS after 19 hours in sinusoid lining cells. The data deriving from Northern blotting, in situ hybridization and immunohistochemical studies, suggest that IL-1ra is formed exclusively in non-parenchymal liver cells.
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PMID:Interleukin 1 receptor antagonist localization exclusively in non-parenchymal cells of the mouse liver. 911 33

We analyzed two distinct phenotypes of Schwann cells (SC), non-differentiated and differentiated, for their ability to produce IL-1alpha and IL-1beta, and to express message for IL-1 receptor antagonist (IL-IRA) and IL-1R type I, in vitro. SC were stimulated with: lipopolysaccharide (LPS), products of activated splenocytes (ASP), products from LPS stimulated SC (SCP), rat recombinant IL-1beta (rrIL-1beta) or dexamethasone. IL-1alpha, IL- 1beta and IL-1RA mRNA levels were highly upregulated after stimulation with LPS, ASP, SCP or rrIL-1beta. SC constitutively expressed low levels of message for IL-1alpha and IL-1beta but not IL-1RA. Specific mRNAs for both IL-1 isotypes were highly upregulated 2 to 4 h after LPS stimulation and then decreased and were undetectable by 24 h. IL-1RA mRNA was detectable after 6 h of LPS stimulation and was maximally upregulated at 24 h. IL-1 gene expression was inducible in both SC phenotypes. IL-1beta could be detected by immunofluorescence in SC, one to three days after LPS stimulation. At the same time IL-1 bioactivity was maximal in SC supernatants. Treatment with either SCP, rrIL-1beta or dexamethasone induced upregulation of IL-1R type I mRNA with maximal expression between 2 to 4 h, in SC. Inducible expression of genes for IL-1alpha, IL-1beta, IL-1RA and IL-1R type I in both differentiated and non-differentiated SC suggest autocrine and paracrine regulation of IL-1 by SC.
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PMID:Induced upregulation of IL-1, IL-1RA and IL-1R type I gene expression by Schwann cells. 911 84

Secretion of cytokines by monocytes has been implicated in the pathogenesis of dialysis-related morbidity. Cytokine generation is presumed to take place in two steps: induction of mRNA transcription for cytokines by C5a and direct membrane contact, followed by lipopolysaccharide (LPS)-induced translation of mRNA (priming/second signal theory, Kidney Int 37: 85-93, 1990). However, the in vitro conditions on which this theory was based differed markedly from clinical dialysis. To test this postulate for routine hemodialysis, 13 patients were studied cross-over with high-flux cuprammonium (CU), cellulose triacetate (CTA), and polysulfon dialyzers, using standard bicarbonate dialysate, as well as CTA with filtered dialysate (fCTA). Besides leukocytes, C3a, C5a, and limulus amebocyte lysate reactivity, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-1RA, soluble TNF receptors, and IL-1 beta mRNA were assessed. Only during dialysis with CU did C5a increase significantly (561 to 8185 ng/ml, P < 0.001). Endotoxin content of standard bicarbonate was higher than filtered dialysate (median, 24.3 and < 5 pg/ml respectively, P = 0.002), whereas limulus amebocyte lysate reactivity was not detected in the blood, except in the case of CU. TNF-alpha levels were elevated before, and remained stable during, dialysis, independent of the modality used. IL-1 beta, IL-6, and mRNA coding for IL-1 beta could not be demonstrated. IL-1RA and soluble TNF receptors (p55/p75) were markedly elevated compared with normal control subjects, but showed no differences between fCTA and CTA. To summarize, no evidence was found for production and release of cytokines by monocytes during clinical high-flux bicarbonate hemodialysis, neither with complement-activating membranes nor with unfiltered dialysate. Therefore, this study sheds some doubt on the relevance of the "priming/second signal" theory for clinical practice. The data presented suggest that reluctance to prescribe the use of high-flux dialyzers, as advocated in many reports, may not be warranted.
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PMID:Cytokine profiles during clinical high-flux dialysis: no evidence for cytokine generation by circulating monocytes. 935 78

The 4555-bp promoter fragment for intracellular interleukin 1 receptor antagonist (4555-bp icIL-1Ra) has recently been demonstrated to regulate gene expression in a cell-type specific manner in vitro in transient transfection studies. To examine the activity of this promoter in vivo, transgenic mice possessing the 4555-bp promoter coupled to the E. coli lacZ reporter gene were created. Expression of endogenous icIL-1Ra and E. coli lacZ mRNA were examined in different tissues by RT-PCR, RNase protection assay and in situ hybridization. In transgenic mice both endogenous icIL-1Ra and E. coli lacZ were co-expressed by keratinocytes and by epithelial cells in different organs of the digestive system. The transgene was also expressed in the brain in four out of five lines, whereas endogenous icIL-1Ra was not detected in this organ. In contrast, only icIL-1Ra mRNA, but not E. coli lacZ mRNA, was detected in lipopolysaccharide (LPS)-stimulated resident peritoneal macrophages from icIL-1Ra promoter transgenic mice. These results indicate that a 4555-bp promoter fragment of human icIL-1Ra appropriately regulates gene transcription in keratinocytes and gastrointestinal epithelial cells in vivo. However, other as yet unidentified regulatory regions influence icIL-1Ra gene expression in macrophages following LPS stimulation.
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PMID:The human intracellular interleukin 1 receptor antagonist promoter appropriately regulates gene expression in keratinocytes and gastrointestinal epithelial cells in vivo. 1043 2

Besides its actions on the regulation of appetite, leptin has also been implicated in regulating reproductive and immune functions. Because leptin-deficient mice are more susceptible to lipopolysaccharide- and tumor necrosis factor-alpha-induced shock, which is associated with lower levels of interleukin 1 receptor antagonist (IL-1Ra), we investigated whether leptin is a direct regulator of IL-1Ra in human monocytes. In human moncytic cells, leptin was capable of inducing a 6- to 10-fold increase in secreted IL-1Ra in a time- and dose-dependent manner. Moreover, leptin induced the messenger RNA for IL-1Ra within 8 h and specifically activated the promoter for this gene. However, leptin had no effect on the expression or secretion of IL-1 in THP-1 cells. This effect of leptin on monocytic cells requires the presence of the functional leptin receptor OB-Rb, which we have shown to be present in human monocytes by RT-PCR and by measuring the activation of the Jak/STAT pathway. In summary, we have demonstrated that leptin is capable of inducing the expression and secretion of IL-1Ra by human monocytes, an effect that is potentially mediated through the presence of functional leptin receptors on these cells. These findings suggest that leptin may have immunomodulatory functions in vivo.
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PMID:Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes. 1115 47

Gene- and signal-specific adaptation/tolerance of blood leukocytes to lipopolysaccharide endotoxin (LPS) occurs during human and animal septicemia. These phenotypes can be modeled in vitro. LPS-TLR4-adapted human THP-1 promonocytic cells cross-adapt to lipoteichoic acid (LTA)-TLR2-induced IL-1beta/TNF-alpha production, suggesting disruption of a common intracellular signaling event(s). A plausible explanation for homologous adaptation of TLR4 with heterologous adaptation of TLR2 is a persistent inactivation and degradation of IRAK1 following TLR4 activation. LTA stimulation of TLR2 also produces homologous adaptation of TLR2 with inactivation of IRAK1, but there is no detectable degradation of IRAK1. Strikingly, such LTA-adapted cells still respond to LPS stimulation of TLR4 with rapid activation and degradation of IRAK1, and robust IL-1beta/TNF-alpha production. Moreover, cells adapted to either LTA- or LPS-production of IL-1beta/TNF-alpha normally produce soluble interleukin 1 receptor antagonist (sIL-1Ra) anti-inflammatory protein when stimulated by either agonist. We conclude that: (i) disruption of a unique TLR2 signaling component upstream of IRAK1, but downstream of TLR2 sensing, induces homologous adaptation to LTA; (ii) disruption of IRAK1 may induce homologous adaptation of TLR4 to LPS and cross-adaptation of TLR2 to LTA; and (iii) TLR2/TLR4 signaling events that control sIL-1Ra translation do not adapt to LPS or LTA, indicating that TLR4 and TLR2 can still function. We present a hypothetical model of adaptation based on a signalsome, with IRAK1 evolving after IRAK4 to regulate TLR4 adaptation tightly.
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PMID:Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes. 1269 17

Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD(50)) for E. coli injected into the bile duct was 50 CFU/animal; the LD(50) for E. coli injected into the portal vein was 5 x 10(7) CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.
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PMID:Infection by gram-negative organisms via the biliary route results in greater mortality than portal venous infection. 1285 2

High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) includes the risk of infectious complications due to neutropenia and therapy-induced immune deviation. In order to understand early immune recovery in this situation, we analyzed the distribution of cell subsets by flow cytometry and we measured cytokine production in a whole blood assay stimulated with lipopolysaccharide (LPS) in order to induce monocyte (MO) activation in 43 patients with solid tumors or lymphoma treated with two cycles of high-dose chemotherapy and PBSCT. Blood was collected at the following time points: before start of mobilization chemotherapy, before and after high-dose chemotherapy, and 10 and 30 days after PBSCT. In the lymphocyte compartment, we found a depletion of B cells and naive T cells and a transitory reduction of natural killer (NK) cells, whereas MO and neutrophils recovered rapidly. However, during early recovery, HLA-DR expression on MO and the percentage of CD16(+) MO was considerably reduced. Production of proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha upon LPS stimulation was severely impaired directly after chemotherapy and unexpectedly remained low during early recovery of myeloid cells, whereas production of IL-1RA was enhanced, indicating a shift of immune competent cells to an anti-inflammatory or anergic state early after PBSCT.
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PMID:Blood leukocyte subsets and cytokine profile after autologous peripheral blood stem cell transplantation. 1296 Oct 30

Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. We investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide or heat-killed Staphylococcus aureus. Concentrations of tumor necrosis factor alpha, interleukin 1 receptor antagonist (IL-1Ra), IL-8, IL-10, IL-18 binding protein, procalcitonin, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria. However, plasma IL-1beta, IL-6, and IL-18 concentrations were significantly higher in patients with sepsis due to gram-positive bacteria. Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-1beta and IL-18 levels more than E. coli lipopolysaccharide stimulation. Microarray analysis revealed at least 359 cross-validated probe sets (genes) significant at the P < 0.001 level whose expression discriminated among gram-negative-organism-stimulated, gram-positive-organism-stimulated, and unstimulated whole-blood leukocytes. The host inflammatory responses to gram-negative and gram-positive stimuli share some common response elements but also exhibit distinct patterns of cytokine appearance and leukocyte gene expression.
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PMID:Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. 1450 May 2


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