UNIPROT:P10145 - FACTA Search

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

Premature activation of the inflammatory processes that mediate human parturition leads to preterm birth, a major clinical problem associated with neonatal morbidity and mortality. Histone deacetylase inhibitors (HDACi) are currently in clinical trials for the treatment of inflammatory disorders. Recent evidence suggests that there may be a therapeutic use for HDACi in the management of preterm birth, with administration of HDACi to pregnant mice shown to delay delivery. Because NF-kappaB is a key orchestrator of the inflammatory response and plays a pivotal role in parturition, it is important to understand how administration of HDACi might affect NF-kappaB activity in human uterine tissues. We show here that the effects of HDACi on nuclear factor-kappaB (NF-kappaB) in human myometrial cells are time-dependent. Short-term exposure to HDACi enhanced interleukin (IL)-1beta-induced NF-kappaB activity as a result of potentiating IkappaB kinase (IKK)beta activity, thereby leading to persistent turnover of IkappaBalpha/epsilon proteins and prolonging NF-kappaB phosphorylation, nuclear localization, and DNA binding. Conversely, long-term HDACi treatments resulted in repression of NF-kappaB DNA binding. Nevertheless, both short- and long-term HDACi treatments inhibited the expression of four labor-associated proinflammatory genes (COX-2, IL-8, IL-6, and RANTES), and this was associated with repression of the proinflammatory transcription factor c-Jun. Together, our data indicate that HDACi exert anti-inflammatory effects in human myometrium and may thus be useful in achieving a myometrial gene expression profile that favors uterine quiescence. However, coadministration of an IKKbeta inhibitor may be both necessary and sufficient to circumvent potential induction of labor-associated pathways that could result from HDACi-induced augmentation of NF-kappaB activity.
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PMID:Histone deacetylase inhibitors exert time-dependent effects on nuclear factor-kappaB but consistently suppress the expression of proinflammatory genes in human myometrial cells. 1837 36

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-8 production caused by leptin in both rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). RASF and OASF expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-8 production. Leptin-mediated IL-8 production was attenuated by OBRl receptor antisense oligonucleotide, JAK2 inhibitor or STAT3 small interference RNA (siRNA). Transfection with insulin receptor substrate (IRS)-1 siRNA or dominant-negative mutant of p85 and Akt or pretreatment with phosphatidylinositol 3-kinase inhibitor (Ly294002 and wortmannin), Akt inhibitor, NF-kappaB inhibitor (PDTC) and NF-kappaB inhibitor peptide also inhibited the potentiating action of leptin. Stimulation of RASF with leptin activated IkappaB kinase alpha/beta (IKK alpha/beta), p65 phosphorylation at Ser(276), p65 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked IL-8 expression. The binding of p65 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 acetylation on the IL-8 promoter was enhanced by leptin, which was inhibited by wortmannin, Akt inhibitor or IRS-1 siRNA. These results suggest that leptin increased IL-8 production in synovial fibroblast via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300.
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PMID:Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. 1850 60

Lyme borreliosis is a spirochetal infection caused by the Borrelia burgdorferi sensu lato complex that can proceed towards an inflammatory joint manifestation known as Lyme arthritis. Production of chemokines orchestrating neutrophil infiltration is supposed to be key to early arthritic pathogenesis. Using PMA-differentiated macrophage-like THP-1 (mTHP-1) cells we identified by antibody array methodology or mRNA analysis IL-8, GRO-alpha, NAP-2, and SDF-1alpha as being among those chemokines that are upregulated by bacterial lysates obtained from B. burgdorferi. Based on these observations, we set out to characterize in detail mechanisms mediating IL-8 release in this cellular model. TLR2 blocking antibodies, analysis of p65 translocation, and electromobility-shift analysis revealed activation of the TLR2/NF-kappaB axis by B. burgdorferi. The functional importance of this pathway was substantiated by suppression of IL-8 after inhibition of IkappaB kinase. Notably, MAP kinases, specifically the MEK1/2-ERK1/2 pathway, were essential for IL-8 secretion. Those data were confirmed by using freshly isolated adherent peripheral blood mononuclear cells. On the contrary, B. burgdorferi-induced IL-8 in mTHP-1 was unlikely related to flagellin, alpha3beta1-integrin signaling, lipopolysaccharide, bacterial DNA, NOD1/NOD2 agonists, or to intermediate production of IL-1beta and TNF-alpha. Induction of IL-8 by B. burgdorferi was not due to amplification of constitutive AP-1 DNA-binding activity detectable in mTHP-1 cells. Data presented herein validate that TLR2, particularly on mTHP-1 cells, holds a central position in mediating IL-8 secretion associated with extracellular B. burgdorferi and beyond that suggest inhibition of IkappaB kinase and MEK1/2 kinases as promising pharmacological strategies aiming at IL-8 in early Lyme arthritis.
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PMID:Systematic analysis highlights the key role of TLR2/NF-kappaB/MAP kinase signaling for IL-8 induction by macrophage-like THP-1 cells under influence of Borrelia burgdorferi lysates. 1857 57

Expression of many pro-inflammatory cytokines is controlled by the NF-kappaB signaling pathway. NF-kappaB is induced by LPS through activation of TLR4. Melanins extracted from fungal, plant and human sources modulate cytokine production and activate NF-kappaB pathway. We showed that a herbal melanin (HM) from Nigella sativa L. modulates cytokine production and suggested it as a ligand for TLR4. In this study we investigated the possibility that the HM-induced cytokine production is via an NF-kappaB signaling pathway. We found that HM induced the degradation of IkappaBalpha, a key step in the activation of NF-kappaB. Moreover, addition of IkappaB kinase (IKK) specific inhibitors effectively inhibited the observed HM-induced production of IL-8 and IL-6 by TLR4-transfected HEK293 cells and THP-1 cells. Our results have also shown that HM induced cleavage of caspase 8, and that this cleavage was partially abrogated by IKK inhibitors. We suggest that HM can modulate the inflammatory response by inducing IL-8 and IL-6 production via TLR4-dependent activation of the NF-kappaB signaling pathway.
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PMID:Herbal melanin activates TLR4/NF-kappaB signaling pathway. 1910 78

Increasing evidence demonstrates that interleukin (IL)-32 is a pro-inflammatory cytokine, inducing IL-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and chemokines via nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase (MAPK), and activating protein (AP)-1 activation. Here we report that IL-32 is expressed and is also functional in human vascular endothelial cells (EC) of various origins. Compared with primary blood monocytes, high levels of IL-32 are constitutively produced in human umbilical vein EC (HUVEC), aortic macrovascular EC, and cardiac as well as pulmonary microvascular EC. At concentrations as low as 0.1 ng/ml, IL-1beta stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNFalpha or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32. IL-1beta-induced IL-32 was reduced by inhibition of the IkappaB kinase-beta/NF-kappaB and ERK pathways. In addition to IL-1beta, pro-coagulant concentrations of thrombin or fresh platelets increased IL-32 protein up to 6-fold. IL-1beta and thrombin induced an isoform-switch in steady-state mRNA levels from IL-32alpha/gamma to beta/epsilon. Adult EC responded in a similar fashion. To prove functionality, we silenced endogenous IL-32 with siRNA, decreasing intracellular IL-32 protein levels by 86%. The knockdown of IL-32 resulted in reduction of constitutive as well as IL-1beta-induced intercellular adhesion molecule-1 (ICAM-1) (of 55% and 54%, respectively), IL-1alpha (of 62% and 43%), IL-6 (of 53% and 43%), and IL-8 (of 46% and 42%). In contrast, the anti-inflammatory/anti-coagulant CD141/thrombomodulin increased markedly when IL-32 was silenced. This study introduces IL-32 as a critical regulator of endothelial function, expanding the properties of this cytokine relevant to coagulation, endothelial inflammation, and atherosclerosis.
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PMID:IL-32-dependent effects of IL-1beta on endothelial cell functions. 1922 41

Extracellular ATP, acting at P2Y and P2X receptors, has recently been shown to contribute to airway inflammation. The aim of our study was to investigate the molecular mechanisms involved in the ATP-dependent regulation of IL-8 production by airway epithelial cells. Treatment of human normal tracheal (NT)-1 cells with ATP or its two analogs, alpha,beta-methylene ATP (alpha,beta-meATP) and 2'- and 3'-O-(4-benzoyl-benzoyl)-ATP (BzATP) activated NF-kappaB through the IkappaB kinase (IKK) complex, a process requiring Ca(2+), calmodulin (CaM), and Ca(2+)/CaM-dependent kinase (CaMK), but independent from phospholipase C. alpha,beta-meATP-induced IKK activation also occurred in the alveolar A549 cell line. Real-time RT-PCR revealed that NT-1 and A549 cells expressed P2X(4), P2X(5),and P2X(6) subtype mRNAs, whereas P2X(7) mRNAs were only detected in NT-1 cells. Polarized human primary nasal epithelial cells expressed all four P2X subtypes. Both alpha,beta-meATP and BzATP caused Ca(2+)-dependent binding of phosphorylated p65 (S536) NF-kappaB subunit to the endogenous IL-8 gene promoter in NT-1 cells. Although these agonists did not induce significant IL-8 gene expression by these cells, they markedly enhanced TNF-alpha-induced NF-kappaB activation, resulting in increased IL-8 expression and release. Application of alpha,beta-meATP or BzATP at the apical side of polarized human primary nasal epithelial cells sufficed to cause CaMK-dependent IL-8 release by these cells. Thus, ATP promotes TNF-alpha-elicited IL-8 expression through P2X ion channel-triggered Ca(2+) entry, leading to CaMK-dependent IKK activation and binding of active p65 to IL-8 gene promoter.
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PMID:A P2X ion channel-triggered NF-kappaB pathway enhances TNF-alpha-induced IL-8 expression in airway epithelial cells. 3300 Sep 73

The mRNA-destabilizing protein tristetraprolin (TTP) negatively regulates adenine- and uridine-rich element (ARE)-containing mRNAs. In A549 pulmonary cells, TTP mRNA and both a approximately 40- and a approximately 45-kDa phosphorylated version of TTP protein were rapidly induced in response to interleukin (IL)-1beta. Analysis with IkappaBalphaDeltaN, a dominant version of inhibitor of kappaBalpha (IkappaBalpha), as well as dominant-negative and small-molecule IkappaB kinase (IKK) inhibitors demonstrated that IL-1beta-induced TTP is nuclear factor-kappaB (NF-kappaB)-dependent. Likewise, TTP expression and formation of the approximately 45-kDa phosphorylated form of TTP are blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). By contrast, and despite a 3- to 4-fold induction of TTP mRNA, the anti-inflammatory glucocorticoid dexamethasone only modestly induced expression of the approximately 40-kDa form of TTP. In the context of IL-1beta, dexamethasone exerted a marginal repressive effect on TTP mRNA expression and more considerably reduced TTP protein. Given a requirement for p38 MAPK in the induction of TTP by IL-1beta, this repressive effect may be explained by repression of the p38 MAPK pathway by dexamethasone. Knockdown of TTP protein by siRNA elevated IL-1beta-induced expression of granulocyte macrophage-colony-stimulating factor (GM-CSF) and IL-8, demonstrating a role for TTP in feedback control. Likewise, knockdown of TTP increased GM-CSF expression in the presence of IL-1beta plus dexamethasone, suggesting that feedback control by TTP also occurs in the context of IL-1beta plus dexamethasone. Taken together, our data demonstrate that NF-kappaB and p38 MAPK are critical to the induction of TTP by IL-1beta and that TTP induction provides feedback control of the ARE-containing genes GM-CSF and IL-8.
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PMID:Regulation of tristetraprolin expression by interleukin-1 beta and dexamethasone in human pulmonary epithelial cells: roles for nuclear factor-kappa B and p38 mitogen-activated protein kinase. 1943 30

Endotoxin tolerance reprograms cell responses to LPS by repressing expression of proinflammatory cytokines, while not inhibiting production of anti-inflammatory cytokines and antimicrobial effectors. Molecular mechanisms of induction and maintenance of endotoxin tolerance are incompletely understood, particularly with regard to the impact of endotoxin tolerization on signalosome assembly, activation of adaptor-kinase modules, and expression of negative regulators of TLR signaling in human cells. In this study, we examined LPS-mediated activation of MyD88-dependent and Toll-IL-1R-containing adaptor inducing IFN-beta (TRIF)-dependent pathways emanating from TLR4 and expression of negative regulators of TLR signaling in control and endotoxin-tolerant human monocytes. Endotoxin tolerization suppressed LPS-inducible TLR4-TRIF and TRIF-TANK binding kinase (TBK)1 associations, induction of TBK1 kinase activity, activation of IFN regulatory factor (IRF)-3, and expression of RANTES and IFN-beta. Tolerance-mediated dysregulation of the TLR4-TRIF-TBK1 signaling module was accompanied by increased levels of suppressor of IkappaB kinase-epsilon (SIKE) and sterile alpha and Armadillo motif-containing molecule (SARM). LPS-tolerant cells showed increased expression of negative regulators Toll-interacting protein (Tollip), suppressor of cytokine signaling (SOCS)-1, IL-1R-associated kinase-M, and SHIP-1, which correlated with reduced p38 phosphorylation, IkappaB-alpha degradation, and inhibited expression of TNF-alpha, IL-6, and IL-8. To examine functional consequences of increased expression of Tollip in LPS-tolerized cells, we overexpressed Tollip in 293/TLR4/MD-2 transfectants and observed blunted LPS-inducible activation of NF-kappaB and RANTES, while TNF-alpha responses were not affected. These data demonstrate dysregulation of TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes.
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PMID:Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling. 1965 1

Expression of the orphan nuclear receptor NR4A2 is controlled by pro-inflammatory mediators, suggesting that NR4A2 may contribute to pathological processes in the inflammatory lesion. This study identifies the chemoattractant protein, interleukin 8 (IL-8/CXCL8), as a molecular target of NR4A2 in human inflammatory arthritis and examines the mechanism through which NR4A2 modulates IL-8 expression. In TNF-alpha-activated human synoviocyte cells, enhanced expression of IL-8 mRNA and protein correspond to temporal changes in NR4A2 transcription and nuclear distribution. Ectopic expression of NR4A2 leads to robust changes in endogenous IL-8 mRNA levels and co-treatment with TNF-alpha results in significant (p<0.001) secretion of IL-8 protein. Transcriptional effects of NR4A2 on the human IL-8 promoter are enhanced in the presence of TNF-alpha, suggesting molecular crosstalk between TNF-alpha signalling and NR4A2. A dominant negative IkappaB kinase antagonizes the combined effects of NR4A2 and TNF-alpha on IL-8 promoter activity. Co-expression of NR4A2 and the p65 subunit of NF-kappaB enhances IL-8 transcription and functional studies indicate that transactivation occurs independently of NR4A2 binding to DNA or heterodimerization with additional nuclear receptors. The IL-8 minimal promoter region is sufficient to support NR4A2 and NF-kappaB/p65 co-operative activity and NR4A2 can interact with NF-kappaB/p65 on a 39bp sequence within this region. In patients treated with methotrexate for active inflammatory arthritis, a reduction in NR4A2 synovial tissue levels correlate significantly (n=10, r=0.73, p=0.002) with changes in IL-8 expression. Collectively, these data delineate an important role for NR4A2 in modulating IL-8 expression and reveal novel transcriptional responses to TNF-alpha in human inflammatory joint disease.
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PMID:Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis. 1973 56

We have previously shown that a frequently downregulated gene, transcription elongation factor A-like 7 (TCEAL7), promoted anchorage-independent growth and modulated Myc activity in ovarian surface epithelial cells immortalized with temperature-sensitive large T antigen and human telomerase reverse transcriptase (OSEtsT/hTERT). Analysis of protein/DNA array showed that TCEAL7 downregulation resulted in an approximately twofold increase in nuclear factor (NF)-kappaB binding to its target DNA sequence. In this study we showed that short hairpin RNA (shRNA)-mediated downregulation of TCEAL7 in two different immortalized OSE cells showed higher NF-kappaB activity, as determined using reporter and gel-shift assays. Transient transfection of TCEAL7 inhibited the activation of NF-kappaB in TCEAL7-downregulated clones, IOSE-523 and in other ovarian cancer cell lines (OVCAR8, SKOV3ip and DOV13), suggesting that TCEAL7 negatively regulates NF-kappaB pathway. Consistent with this observation, TCEAL7-downregulated clones showed higher levels of NF-kappaB targets, such as pro-proliferative (cyclin-D1 and cMyc), pro-angiogenic (interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF)), inflammatory (intercellular adhesion molecule 1 (ICAM-1) and cyclooxygenase-2 (Cox-2)) and anti-apoptotic (B-cell lymphoma-extra large (Bcl-xl)) genes when compared with vector controls. Inhibition of NF-kappaB by IkappaB kinase (IKK) inhibitor (BMS 345541) attenuated cell survival and proliferation of TCEAL-knockdown clones. Although TCEAL7 inhibited p65 transcriptional activity, it did not modulate the cytoplasmic signaling of the NF-kappaB pathway, by itself or by tumor necrosis factor-alpha (TNF-alpha). Chromatin immunoprecipitation (ChIP) assays revealed increased recruitment of p65 and p300 to the promoters of IL-8 and IL-6 in TCEAL7-downregulated clones. Collectively, these results indicate a novel role for TCEAL7 in the negative regulation of NF-kappaB signaling at the basal level by modulating transcriptional activity of NF-kappaB on its target gene promoters, potentially providing a novel mechanism by which NF-kappaB activity may be deregulated in ovarian cancer cells.
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PMID:TCEAL7, a putative tumor suppressor gene, negatively regulates NF-kappaB pathway. 1996 55

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