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)

The processing of pro-opiomelanocortin (POMC) to generate bioactive ACTH in the anterior pituitary is mediated by prohormone convertase 1 (PC1). Leukemia inhibitory factor (LIF) and interleukin 6 (IL-6), two cytokines sharing the common gp130 receptor subunit and functioning through activation of the intracellular JAK/STAT pathway, induce POMC synthesis and ACTH release. We investigated the effects of LIF and IL-6 on PC1 expression and its subsequent processing of POMC. A significant time-dependent up-regulation of both PC1 protein and mRNA by LIF and IL-6 was seen in mouse corticotroph AtT-20 cells. IL-6 or LIF increased the synthesis of ACTH-related products with a concomitant increase in bioactive 5 and 13 kDa ACTH indicating coordinated regulation of substrate and processing enzyme. AtT-20 cells transiently transfected with a human PC1-promoter-luciferase reporter construct and treated with LIF or IL-6 showed significantly increased luciferase activity. Additionally, lipopolysaccharide (LPS) administration to rats resulted in an increase in both pituitary PC1 and POMC mRNA. These findings suggest that the ACTH increase induced by LIF and IL-6 is due to both increased POMC synthesis as well as increased POMC processing by up-regulation of PC1. These two coordinately regulated processing events probably exert central roles in the pathophysiological response to some stresses, such as inflammatory stress.
 ...
PMID:Regulation of prohormone convertase 1 (PC1) by gp130-related cytokines. 1063 Apr 14

Interleukin (IL)-6 is important for host defense against various pathogens. The IL-6 receptor (IL-6R) complex consists of a ligand-binding component (IL-6R) and a signal-transducing component (gp130). In a study designed to obtain insight into the regulation of this receptor complex during inflammation, 8 healthy subjects received an intravenous injection of lipopolysaccharide (LPS; 4 ng/kg), and receptor expression was determined on blood leukocytes by use of fluorescence-activated cell cytometry. LPS induced a transient decrease in monocyte and granulocyte IL-6R expression but did not influence gp130. The plasma concentrations of soluble IL-6R and soluble gp130 did not change after LPS administration. Expression of the receptor for leukemia inhibitory factor, a member of the IL-6R family, remained unaltered after LPS injection. In whole blood in vitro, LPS and gram-positive stimuli and proinflammatory cytokines were capable of down-modulating the IL-6R. Monocytes and granulocytes may down-regulate IL-6R at their surface upon their first interaction with bacterial antigens.
 ...
PMID:Endotoxin down-regulates monocyte and granulocyte interleukin-6 receptors without influencing gp130 expression in humans. 1072 May 31

Peripheral blood monocytes are common precursor cells of dendritic cells (DCs) and macrophages. We have searched for factors with the potential to regulate the differentiation of monocytes to DCs and macrophages. When CD14+ monocytes are cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) 4, the CD14+CD1a- population, which consists of macrophages, was found in the serum-containing cultures but not in the serum-free cultures. Addition of IL-6 receptor-neutralizing monoclonal antibody (mAb) or gp130-neutralizing mAb to the serum-containing cultures resulted in a decreased population of CD14+CD1a- cells. An increase in the CD14+CD1a- population with reduction in CD14-CD1a+ DCs was observed with the addition of IL-6 to cultures, whereas IL-11, leukaemia inhibitory factor, oncostatin M or macrophage colony-stimulating factor did not affect the differentiation of monocytes in the presence of GM-CSF plus IL-4. This effect of IL-6 was blocked by tumour necrosis factor alpha (TNF-alpha), lipopolysaccharide (LPS), IL-1beta, CD40 ligand (CD40L) and transforming growth factor beta1 (TGF-beta1). Among these factors, TNF-alpha was most potent in interfering with the action of IL-6. These results suggest that IL-6 inhibits the differentiation of monocytes to DCs by promoting their differentiation toward macrophages, which is modulated by factors such as TNF-alpha, LPS, IL-1beta, CD40L and TGF-beta1.
 ...
PMID:Activity of interleukin 6 in the differentiation of monocytes to macrophages and dendritic cells. 1084 14

Cytokine-inducible proteins named as suppressors of cytokine signaling (SOCS) are rapidly induced by interleukin-6 (IL-6) and other members sharing the gp130 receptor subunit after activation of the Janus kinases (JAK) and the signal transducers and activators of transcription (STAT). These inhibitory proteins generally prevent tyrosine phosphorylation of IL-6 receptor signaling subunit gp130, specific JAK and STAT or in acting at steps distal to JAK activation. Expression of these inhibitory proteins is therefore a useful tool to investigate the signaling events occurring in the brain during immunogenic stimuli that involve cytokines of the IL-6 family. This study investigated the effect of ip lipopolysaccharide (LPS) administration on the expression of one key member of the SOCS family, SOCS-3, in both rats and mice. In rats, the endotoxin caused a profound transcriptional activation of the inhibitory factor in the circumventricular organs subfornical organ, organum vasculosum of the lamina terminalis, arcuate nucleus/median eminence, area postrema, choroid plexus, leptomeninges, ependymal lining cells, and along the endothelium of the brain blood vessels. The hybridization signal for SOCS-3 messenger RNA was low at 1 h, but robust at 3 and 6 h and declined to return to basal levels 12 h after the single ip LPS injection. The pattern of SOCS-3 expression was similar in the brain of wild-type mice, although induction of the inhibitory factor was no longer observed in the ependymal lining cells of the cerebral ventricles and the blood microvessels of IL-6-deficient animals at all the times evaluated, i.e. from 1-8 h post-LPS injection. The endothelium of the brain capillaries also exhibited up-regulation of both IL-6 receptor and gp130 subunits during systemic inflammation, which allowed SOCS-3 expression in response to circulating IL-6. The present data indicate that the JAK/STAT transduction pathways that lead to SOCS-3 transcription are activated within cells accessible from the blood circulation, but not within deep parenchymal elements of the brain during endotoxemia. Induction of SOCS-3 followed the cascade of events that take place during the acute phase response and the contribution of IL-6 in activating the inhibitory factor is site specific and not generalized throughout the central nervous system.
 ...
PMID:Selective involvement of interleukin-6 in the transcriptional activation of the suppressor of cytokine signaling-3 in the brain during systemic immune challenges. 1101 31

The host response to peripheral inflammation induces fever and behavioural depression that are supposed to be centrally mediated by cytokines. Several proinflammatory cytokines activate 'signal transducer and activator of transcription' 3 (STAT3) via gp130-like receptor signaling. In order to determine which cells in the rat brain and pituitary are activated during bacterial inflammation, we investigated in a spatiotemporal manner the activation of STAT3 in these organs following peripheral lipopolysaccharide (LPS) challenge. Under basal conditions, STAT3 immunoreactivity was observed in neurones and some glial cells throughout the brain. Two hours after the administration of LPS, nuclear localisation of STAT3 (hallmark of activation) was observed in zones at the interface between brain and blood or cerebrospinal fluid such as pituitary, ependymal layer, meninges, glia limitans, circumventricular organs and surrounding nervous parenchyma. Four hours after LPS, the nuclear activation of STAT3 propagated to cells located inside the parenchyma (cortex, hypothalamus, corpus callosum and hippocampus among others) and declined 8 h after treatment. Double labelling of STAT3 and glial fibrillary acidic protein identified activated cells in the parenchyma as astrocytes. These data show that STAT3 is activated in the pituitary and in brain astrocytes after a peripheral LPS challenge as demonstrated by immunohistochemistry. Astrocytes may therefore play a key role in the brain response to peripheral inflammation.
 ...
PMID:Spatiotemporal analysis of signal transducer and activator of transcription 3 activation in rat brain astrocytes and pituitary following peripheral immune challenge. 1207 13

Adrenocorticotropic hormone (ACTH) release from anterior pituitary corticotropes is greatly increased during peripheral inflammation induced by lipopolysaccharide (LPS) administration. Interleukin-6 (IL-6) is thought to participate in LPS-induced ACTH release, but whether or not corticotropes are directly targeted by this cytokine is unclear. Therefore, we investigated the expression and activation of IL-6 signaling components in the pituitary of rats 2 and 4 h after administration of LPS (250 microg/kg). Intraperitoneal LPS treatment provoked the nuclear translocation of signal transducer and activator of transcription 3 (STAT-3) and Fos expression in the anterior pituitary lobe, as demonstrated by immunohistochemistry. By using in situ hybridization, we demonstrated that suppressor of cytokine signaling 3 (SOCS-3) and c-fos mRNAs were significantly induced by the LPS treatment in the anterior lobe of the pituitary. Dual in situ hybridization revealed that most corticotropes expressed IL-6 receptor and gp130 mRNAs, and that 2 h after LPS treatment, SOCS-3 and c-fos mRNAs were induced in corticotropes. Our results suggest that LPS-induced IL-6 could regulate the hypothalamo-pituitary-adrenal axis by directly targeting corticotropes during peripheral inflammation.
 ...
PMID:In vivo activation of the interleukin-6 receptor/gp130 signaling pathway in pituitary corticotropes of lipopolysaccharide-treated rats. 1262 39

Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
 ...
PMID:Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide. 1273 Sep 64

Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.
 ...
PMID:IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. 1277 70

The role of IL-6 in the pathogenesis of pituitary adenomas is unclear, as tumor biology is difficult to study in primary culture. We have shown here that the human pituitary cell line HP75 synthesizes IL-6 mRNA and expresses and secretes IL-6 (6167 +/- 56 pg/ml/72 h for 30,000 cells). IL-6 receptor (IL-6R) mRNA was identified by in situ hybridization and RT-PCR. Exogenous IL-6 in low dose (1 ng/ml) stimulated, whereas higher doses (100 ng/ml) inhibited, growth. This diverse effect occurs in other cell types as a result of receptor down-regulation. Cell growth was inhibited by IL-6-blocking antibody (76 +/- 6.5% inhibition; P < 0.0001). This demonstrates that IL-6 is an important growth regulator in HP75 cells, having an autocrine growth stimulatory effect under basal conditions. IL-1alpha and dibutyryl cAMP stimulated and dexamethasone inhibited IL-6 secretion; however, bacterial lipopolysaccharide, forskolin, and cholera toxin had no effect. This implies that there is a defect in the control of IL-6 secretion. Soluble IL-6R was not detected, but soluble gp130 receptor was present in the conditioned medium. Stimulation of cleavage of soluble IL-6R from the membrane-bound IL-6R could not be induced by phorbol ester or dexamethasone. Whether IL-6 has a similar effect in human pituitary adenomas requires further investigation.
 ...
PMID:Expression of interleukin-6 and its effects on growth of HP75 human pituitary tumor cells. 1455 77

Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.
 ...
PMID:Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. 1456 54


<< Previous 1 2 3 4 5 6 Next >>