Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viral infection is one of the leading causes of brain encephalitis and meningitis. Recently, it was reported that Toll-like receptor-3 (TLR3) induces a double-stranded RNA (dsRNA)-mediated inflammatory signal in the cells of the innate immune system, and studies suggested that dsRNA may induce inflammation in the central nervous system (CNS) by activating the CNS-resident glial cells. To explore further the connection between dsRNA and inflammation in the CNS, we have studied the effects of dsRNA stimulation in astrocytes. Our results show that the injection of polyinosinic-polycytidylic acid (poly(I:C)), a synthetic dsRNA, into the striatum of the mouse brain induces the activation of astrocytes and the expression of TNF-alpha, IFN-beta, and IP-10. Stimulation with poly(I:C) also induces the expression of these proinflammatory genes in primary astrocytes and in CRT-MG, a human astrocyte cell line. Furthermore, our studies on the intracellular signaling pathways reveal that poly(I:C) stimulation activates IkappaB kinase (IKK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in CRT-MG. Pharmacological inhibitors of nuclear factor-kappaB (NF-kappaB), JNK, ERK, glycogen synthase kinase-3beta (GSK-3beta), and dsRNA-activated protein kinase (PKR) inhibit the expression of IL-8 and IP-10 in astrocytes, indicating that the activation of these signaling molecules is required for the TLR3-mediated chemokine gene induction. Interestingly, the inhibition of PI3 kinase suppressed the expression of IP-10, but upregulated the expression of IL-8, suggesting differential roles for PI3 kinase, depending on the target genes. These data suggest that the TLR3 expressed on astrocytes may initiate an inflammatory response upon viral infection in the CNS.
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PMID:TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. 1626 67

Nuclear factor-kappaB (NFkappaB) is an inducible transcription factor that plays a key role in regulating the expression of a wide range of immune and inflammatory response genes. The activity of NFkappaB is controlled at multiple levels, including cytoplasmic retention with inhibitor of kappaB (IkappaB) proteins in the basal state. Persistent activation of the transcription factor is seen in numerous chronic inflammatory disease states, and we have previously demonstrated sustained activation of NFkappaB in human glial cells upon stimulation with interleukin (IL)-1beta. In these cells, NFkappaB retains DNA binding activity for up to 72 h despite the presence of resynthesized IkappaBalpha and in the absence of IkappaBbeta. Here we characterized the apparent inability of newly synthesized IkappaBalpha to terminate activation of NFkappaB in glial cells. We showed unexpectedly that newly synthesized IkappaBalpha can enter the nucleus, interact with the NFkappaB subunit p65, and export it to the cytoplasm. However, in vitro analysis of enzyme activity demonstrates that IL-1beta causes the long term activation of the IkappaB kinase complex leading to chronic phosphorylation of the newly synthesized IkappaBalpha signal response domain and persistent activation of NFkappaB. Such sustained activation of NFkappaB is dependent on the continuous presence and activity of IL-1beta. Interestingly, the sustained nature of NFkappaB activity is promoter type-specific. Chromatin immunoprecipitation studies revealed that p65 is detected at the promoters of both intercellular adhesion molecule-1 and IL-8 1 h following IL-1beta stimulation but is only found at the latter at 24 h. The functional significance of this finding is indicated by the transient induction of intercellular adhesion molecule-1 mRNA, but more sustained induction of IL-8 expression, by IL-1beta. These studies thus demonstrated that persistent IL-1 signaling causes sustained activation of NFkappaB in a promoter-specific manner in human glial cells, leading to prolonged induction of selective pro-inflammatory genes. This is likely to make a key contribution to chronic inflammatory conditions of the brain.
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PMID:Persistent interleukin-1beta signaling causes long term activation of NFkappaB in a promoter-specific manner in human glial cells. 1645 61

Helicobacter pylori induces NF-kappaB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-kappaB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-kappaB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-kappaB signaling intermediate molecules was evaluated in H. pylori-induced IkappaBalpha phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IkappaB kinase, TGF-beta-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-kappaB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IkappaBalpha phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-kappaB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.
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PMID:MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. 1651 50

The neutrophil is pivotal to ANCA vasculitis pathogenesis. Fever frequently complicates ANCA diseases. This study investigated the effects of short-term heat exposure on apoptosis in neutrophils that were treated with LPS, GM-CSF, IL-8, and dexamethasone. All compounds delayed apoptosis. Heat abrogated the apoptosis-delaying effect of LPS without affecting constitutive apoptosis or delayed apoptosis by GM-CSF, IL-8, or dexamethasone. The heat effect was dose dependent over the 39 to 42 degrees C range. NF-kappaB but not extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), or phosphatidylinositol 3-kinase/Akt controlled LPS-delayed apoptosis. Furthermore, LPS-induced IkappaBalpha degradation, DNA binding, and NF-kappaB-dependent gene transcription activation were abrogated by short-term heat. When core temperatures were raised to 40.5 degrees C for 30 min in mice, LPS-induced neutrophil NF-kappaB activation also was prevented. Short-term heat removed heat-shock protein 90 from the IkappaB kinase complex, resulting in failure of LPS-induced IkappaB kinase activation. Despite delayed apoptosis, ANCA antigen expression was increased in LPS-treated neutrophils. ANCA antigen increase was prevented by p38 MAPK inhibition and by heat exposure. Heat exposure did not inhibit LPS-induced p38 MAPK phosphorylation. Instead, apoptosis-mediated p38 MAPK degradation was accelerated, thereby decreasing the p38 MAPK that was available for LPS-mediated ANCA antigen upregulation. These data suggest that fever-like temperatures modulate neutrophil behavior in this disease.
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PMID:Fever-like temperatures affect neutrophil NF-kappaB signaling, apoptosis, and ANCA-antigen expression. 1659 88

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation. However, because patients with COPD and certain patients with asthma show little or no therapeutic benefit from existing corticosteroid therapies, there is an urgent need for novel anti-inflammatory strategies. The transcription factor nuclear factor-kappaB (NF-kappaB) is central to inflammation and is necessary for the expression of numerous inflammatory genes. Proinflammatory cytokines, including interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate the IkappaB kinase complex (IKK) to promote the degradation of inhibitory IkappaB proteins and activate NF-kappaB. This pathway and, in particular, the main IkappaB kinase, IKK2, are now considered prime targets for novel anti-inflammatory drugs. Therefore, we have used adenoviral overexpression to demonstrate NF-kappaB and IKK2 dependence of key inflammatory genes, including intercellular adhesion molecule (ICAM)-1, cyclooxygenase-2, IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), growth-regulated oncogene-alpha (GROalpha), neutrophil-activating protein-2 (NAP-2), and epithelial neutrophil activating peptide 78 (ENA-78) in primary human airways smooth muscle cells. Because this cell type is central to the pathogenesis of airway inflammatory diseases, these data predict a beneficial effect of IKK2 inhibition. These validated outputs were therefore used to evaluate the novel IKK inhibitors N-(6-chloro-9H-beta-carbolin-8-yl) nicotinamide (PS-1145) and N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methyl-nicotinamide (ML120B) on IL-1beta and TNFalpha-induced expression, and this was compared with the corticosteroid dexamethasone. As observed above, ICAM-1, IL-6, IL-8, GM-CSF, RANTES, MCP-1, GROalpha, NAP-2, and ENA-78 expression was reduced by the IKK inhibitors. Furthermore, this inhibition was either as effective, or for ICAM-1, MCP-1, GROalpha, and NAP-2, more effective, than a maximally effective concentration of dexamethasone. We therefore suggest that IKK inhibitors may be of considerable benefit in inflammatory airways diseases, particularly in COPD or severe asthma, in which corticosteroids are ineffective.
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PMID:Validation of the anti-inflammatory properties of small-molecule IkappaB Kinase (IKK)-2 inhibitors by comparison with adenoviral-mediated delivery of dominant-negative IKK1 and IKK2 in human airways smooth muscle. 1668 66

Intestinal epithelial cells are known to upregulate the expression of several chemokines in response to stimulation with bacterial toxin. However, the cellular mechanisms of Clostridium difficile toxin A-induced mucosal inflammation have not yet been fully elucidated. In this study, we investigated whether nuclear factor-kappa B (NF-kappaB) could regulate chemokine expression in intestinal epithelial cells. Toxin A increased the levels of NF-kappaB complexes containing p65/p50 heterodimers and p65/p65 homodimers. Concurrently, toxin A decreased the levels of IkappaBalpha. Toxin A stimulation also increased the signals of phosphorylated IkappaB kinase (IKK)alpha/beta and NF-kappaB-inducing kinase (NIK). In the toxin A-stimulated HT-29 cells, the suppression of IKK or NIK inhibited the upregulation of downstream target genes of NF-kappaB such as IL-8 and monocyte-chemotactic protein (MCP)-1 and similarly, inhibition of NF-kappaB also downregulated the expression of IL-8, growth-related oncogene-alpha, and MCP-1. These results suggest that NF-kappaB signalling events may be involved in the inflammatory responses to toxin A produced by toxigenic C. difficile.
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PMID:NF-kappa B activation pathway is essential for the chemokine expression in intestinal epithelial cells stimulated with Clostridium difficile toxin A. 1676 99

In this study, we examined the regulation of NF-kappaB activation and IL-8/CXCL8 expression by thrombin in human lung epithelial cells (EC). Thrombin caused a concentration-dependent increase in IL-8/CXCL8 release in a human lung EC line (A549) and primary normal human bronchial EC. In A549 cells, thrombin, SFLLRN-NH2 (a protease-activated receptor 1 (PAR1) agonist peptide), and GYPGQV-NH2 (a PAR4 agonist peptide), but not TFRGAP-NH2 (a PAR3 agonist peptide), induced an increase in IL-8/CXCL8-luciferase (Luc) activity. The thrombin-induced IL-8/CXCL8 release was attenuated by D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (a thrombin inhibitor), U73122 (a phosphoinositide-phospholipase C inhibitor), Ro-32-0432 (a protein kinsase C alpha (PKC alpha) inhibitor), an NF-kappaB inhibitor peptide, and Bay 117082 (an IkappaB phosphorylation inhibitor). Thrombin-induced increase in IL-8/CXCL8-Luc activity was inhibited by the dominant-negative mutant of c-Src and the cells transfected with the kappaB site mutation of the IL-8/CXCL8 construct. Thrombin caused time-dependent increases in phosphorylation of c-Src at tyrosine 416 and c-Src activity. Thrombin-elicited c-Src activity was inhibited by Ro-32-0432. Stimulation of cells with thrombin activated IkappaB kinase alphabeta (IKK alphabeta), IkappaB alpha phosphorylation, IkappaB alpha degradation, p50 and p65 translocation from the cytosol to the nucleus, NF-kappaB-specific DNA-protein complex formation, and kappaB-Luc activity. Pretreatment of A549 cells with Ro-32-4032 and the dominant-negative mutant of c-Src DN inhibited thrombin-induced IKK alphabeta activity, kappaB-Luc activity, and NF-kappaB-specific DNA-protein complex formation. Further studies revealed that thrombin induced PKC alpha, c-Src, and IKK alphabeta complex formation. These results show for the first time that thrombin, acting through PAR1 and PAR4, activates the phosphoinositide-phospholipase C/PKC alpha/c-Src/IKK alphabeta signaling pathway to induce NF-kappaB activation, which in turn induces IL-8/CXCL8 expression and release in human lung EC.
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PMID:c-Src mediates thrombin-induced NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells. 1692 Sep 85

Rhinovirus infections cause the majority of acute exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease, with increased pro-inflammatory cytokine production by infected bronchial epithelial cells contributing to disease pathogenesis. Theses diseases are a huge cause of morbidity worldwide, and contribute a major economic burden to healthcare costs. Current steroid based treatments are only partially efficient at controlling virus induced inflammation, which remains an unmet therapeutic goal. Although NF-kappaB has been implicated, the precise mechanisms of rhinovirus induction of pro-inflammatory gene expression in bronchial epithelial cells are unclear. We hypothesised that rhinovirus replication and generation of dsRNA was an important process of pro-inflammatory cytokine induction. Using pharmalogical (2-aminopurine and a new small molecule inhibitor) and genetic inhibition of the dsRNA binding kinase protein kinase R, striking inhibition of dsRNA (polyrIC) and rhinovirus induced CCL5, CXCL8 and IL-6 protein was observed. Using confocal microscopy, rhinovirus induced protein kinase R phosphorylation co-located with NF-kappaB p65 nuclear translocation. Focusing on CXCL8, both rhinovirus infection and dsRNA treatment required IkappaB kinase-beta for induction of CXCL8. Analysis of cis-acting sites in the CXCL8 promoter revealed that both rhinovirus infection and dsRNA treatment upregulated CXCL8 promoter activation via NF-kappaB and NF-IL6 binding sites. Together, the results demonstrate the importance of dsRNA in induction of pro-inflammatory cytokines by rhinoviruses, and suggest that protein kinase R is involved in NF-kappaB mediated gene transcription of pro-inflammatory cytokines via IkappaB kinase-beta. These molecules regulating rhinovirus induction of inflammation represent therapeutic targets.
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PMID:Protein kinase R, IkappaB kinase-beta and NF-kappaB are required for human rhinovirus induced pro-inflammatory cytokine production in bronchial epithelial cells. 1698 99

Human herpesvirus 8 (HHV-8) is considered the causative agent of Kaposi sarcoma, a highly vascularized neoplasm characterized by spindle-shaped cells of endothelial origin and inflammatory cell infiltration. The cell transforming ability of HHV-8 has been associated with the activation of NF-kappaB, a nuclear factor playing a pivotal role in promoting inflammation and cell proliferation; however, little is known about NF-kappaB activation during acute HHV-8 infection. In the present study, we used a recently established in vitro model of HHV-8 acute productive infection in endothelial cells to investigate the effect of HHV-8 on NF-kappaB activity and function. HHV-8 rapidly and potently induced NF-kappaB activity in endothelial cells via stimulation of the IkappaB kinase (IKK). Following IKK activation, HHV-8 selectively triggered the production of high levels of monocyte chemoattractant protein 1 (MCP-1), whereas it did not affect the expression of other NF-kappaB-dependent proinflammatory proteins, including TNF-alpha, IL-8, and RANTES. Deletion of NF-kappaB-binding sites in the MCP-1 enhancer resulted in significant inhibition of HHV-8-induced transcription. Furthermore, MCP-1 production was accompanied by virus-induced capillary-like structure formation at early stages of infection. The results suggest that HHV-8-induced MCP-1 may play an important role in promoting inflammation and pathogenic angiogenesis typical of HHV-8-associated lesions.
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PMID:Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kappaB pathway. 1713 27

Cystic fibrosis (CF) is characterized by prolonged and excessive inflammatory responses in the lung and increased activation of NF-kappaB. Parthenolide is a sesquiterpene lactone derived from the plant feverfew, which has been used in folk medicine for anti-inflammatory activity. Several studies suggest that this compound inhibits the NF-kappaB pathway, but the exact site is controversial. We hypothesized that parthenolide might ameliorate the excessive inflammatory response in CF models by inhibiting activation of NF-kappaB. This was tested in vitro, using two pairs of cell lines with defective versus normal CF transmembrane conductance regulator (CFTR) (antisense/sense transfected 16 HBE and IB-3/S9), and in vivo, using CFTR-knockout (KO) mice. All cell lines were pretreated with parthenolide and then stimulated with IL-1beta and/or TNF. Parthenolide significantly inhibited IL-8 secretion induced by these cytokines and prevented NF-kappaB activation, IkappaBalpha degradation, and IkappaB Kinase complex activity. CFTR-KO and wild-type mice were pretreated with parthenolide or vehicle alone then challenged intratracheally with LPS. Bronchoalveolar lavage was performed 3, 6, and 8 h later. Parthenolide pretreatment inhibited PMN influx as well as cytokine and chemokine production. This was also associated with inhibition of IkappaBalpha degradation and NF-kappaB activation. We thus conclude that parthenolide inhibits IkappaB kinase, resulting in stabilization of cytoplasmic IkappaBalpha, which in turn leads to inhibition of NF-kappaB translocation and attenuation of subsequent inflammatory responses. IkappaB kinase may be a good target, and parthenolide and/or feverfew might be promising treatments for the excessive inflammation in CF.
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PMID:Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice. 1727 24


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