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)

In vitro infection with dengue virus induces interleukin (IL)-8 secretion, which increases endothelial cell permeability; this has been proposed as a mechanism for plasma leakage in dengue hemorrhagic fever. We studied the mechanisms of IL-8 induction, using luciferase reporter constructs, and the effect of pharmacological inhibitors of either IL-8 secretion or nuclear factor- kappa B (NF-kappa B) activation on IL-8 induction by dengue 2 virus (DEN2V) infection. IL-8 induction by DEN2V infection was associated with activation of NF- kappa B and activator protein-1 (AP-1) in HEK293A cells but only with activation of AP-1 in HepG2 cells. Treatment with SB203580, a mitogen-activated protein kinase inhibitor, and rolipram, a phosphodiesterase IV inhibitor, partially inhibited DEN2V-induced IL-8 secretion in HEK293A cells but increased DEN2V-induced IL-8 secretion in HepG2 cells. In contrast, treatment with dexamethasone increased DEN2V-induced IL-8 secretion in HEK293A cells but had no effect on DEN2V-induced IL-8 secretion in HepG2 cells. These results demonstrate that anti-inflammatory drugs have variable effects on IL-8 secretion in different cell types during DEN2V infection.
 ...
PMID:Cell type-specific mechanisms of interleukin-8 induction by dengue virus and differential response to drug treatment. 1654 47

Intracolonic administration of trinitrobenzene sulfonic acid in mice causes inflammation in the colon that is accompanied by increased expression of proinflammatory cytokines and of the substance P (SP), neurokinin 1 receptor (NK-1R) in the proximal mesenteric fat depot. We also investigated whether human mesenteric preadipocytes contain NK-1R and examined the functional consequences of exposure of these cells to SP as it relates to proinflammatory signaling. We found that human mesenteric preadipocytes express NK-1R both at the mRNA and protein levels. Exposure of human mesenteric preadipocytes to SP increased NK-1R mRNA and protein expression by 3-fold, and stimulated IL-8 mRNA expression and protein secretion. This effect was abolished when these cells were pretreated with the specific NK-1R antagonist CJ 012,255. Moreover, human mesenteric preadipocytes transfected with a luciferase promoter/reporter system containing the IL-8 promoter with a mutated NF-kappaB site lost their ability to respond to SP, indicating that SP-induced IL-8 expression is NF-kappaB-dependent. This report indicates that human mesenteric preadipocytes contain functional SP receptors that are linked to proinflammatory pathways, and that SP can directly increase NK-1R expression. We speculate that mesenteric fat depots may participate in intestinal inflammatory responses via SP-NK-1R-related pathways, as well as other systemic responses to the presence of an ongoing inflammation of the colon.
 ...
PMID:Induction of colitis causes inflammatory responses in fat depots: evidence for substance P pathways in human mesenteric preadipocytes. 1654 70

Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-alpha or IL-1beta, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-kappaB activation was assessed by NF-kappaB-driven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-alpha and IL-1beta significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-kappaB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-alpha or IL-1beta augmented NF-kappaB activation and IL-8 production in response to PGN or LTA. Both PGN- and LTA-induced NF-kappaB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-alpha or IL-1beta primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system.
 ...
PMID:Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. 1661 4

Generation of mixtures of small interfering (si) RNAs by recombinant dicer avoids selection of efficient target sites within mRNAs but little is known about off-target effects of this approach. Using recombinant human dicer we generated siRNA mixtures (dsiRNA) directed against the protein kinase TAK1 and its subunit TAB1, important upstream molecules in the pathways activated by IL-1, TNF, and toll-like receptors (TLR). dsiRNA against TAK1 or TAB1 significantly suppressed their target proteins as well as TAK1-mediated activation of NFkappaB, p38 MAPK, and JNK, and of IL-8 transcription. However, microarray analysis of 136 endogenous inflammatory genes revealed that dsiRNA against TAB1 or TAK1 did not suppress IL-1 or TNF-induced genes but rather induced a broader range of 15 inflammatory genes as well as seven known interferon-response genes. The same genes were induced by dsiRNA directed against luciferase but not by a synthetic control siRNA molecule. Hence, our results show that complex mixtures of siRNA induce an inflammatory gene response that is independent from TAK1-mediated signal transduction. In the light of the increasing usage of enzymatically prepared libraries of siRNA these results provide important insight into potential off-target effects of this approach.
 ...
PMID:Small interfering RNAs generated by recombinant dicer induce inflammatory gene expression independent from the TAK1-NFkappaB-MAPK signaling pathways. 1684 36

Cigarette smoke is a powerful inducer of inflammatory responses resulting in disruption of major cellular pathways with transcriptional and genomic alterations driving the cells towards carcinogenesis. Cell culture and animal model studies indicate that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol present in green tea, possesses potent anti-inflammatory and antiproliferative activity capable of selectively inhibiting cell growth and inducing apoptosis in cancer cells without adversely affecting normal cells. Here, we demonstrate that EGCG pretreatment (20-80 microM) of normal human bronchial epithelial cells (NHBE) resulted in significant inhibition of cigarette smoke condensate (CSC)-induced cell proliferation. Nuclear factor-kappaB (NF-kappaB) controls the transcription of genes involved in immune and inflammatory responses. In most cells, NF-kappaB prevents apoptosis by mediating cell survival signals. Pretreatment of NHBE cells with EGCG suppressed CSC-induced phosphorylation of IkappaBalpha, and activation and nuclear translocation of NF-kappaB/p65. NHBE cells transfected with a luciferase reporter plasmid containing an NF-kappaB-inducible promoter sequence showed an increased reporter activity after CSC exposure that was specifically inhibited by EGCG pretreatment. Immunoblot analysis showed that pretreatment of NHBE cells with EGCG resulted in a significant downregulation of NF-kappaB-regulated proteins cyclin D1, MMP-9, IL-8 and iNOS. EGCG pretreatment further inhibited CSC-induced phosphorylation of ERK1/2, JNK and p38 MAPKs and resulted in a decreased expression of PI3K, AKT and mTOR signaling molecules. Taken together, our data indicate that EGCG can suppress NF-kappaB activation as well as other pro-survival pathways such as PI3K/AKT/mTOR and MAPKs in NHBE cells, which may contribute to its ability to suppress inflammation, proliferation and angiogenesis induced by cigarette smoke.
 ...
PMID:Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. 1686 72

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.
 ...
PMID:c-Src mediates thrombin-induced NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells. 1692 Sep 85

The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD(2) activation and the potential contribution of PKD(2) in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD(2), as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD(2) activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD(2) activity. LPA induced a striking increase in IL-8 production and stimulated NF-kappaB activation, as measured by NF-kappaB-DNA binding, NF-kappaB-driven luciferase reporter activity, and IkappaBalpha phosphorylation. PKD(2) gene silencing utilizing small interfering RNAs targeting distinct PKD(2) sequences dramatically reduced LPA-stimulated NF-kappaB promoter activity and IL-8 production. PKD(2) activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-kappaB-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.
 ...
PMID:Protein kinase D2 mediates lysophosphatidic acid-induced interleukin 8 production in nontransformed human colonic epithelial cells through NF-kappaB. 1692 71

Mast cells play an important role in the pathogenesis of allergic diseases through the release of inflammatory mediators such as histamine, cysteinyl leukotrienes, cytokines, and chemokines. Flavonoids, like fisetin are naturally occurring molecules with antioxidant, cytoprotective, and anti-inflammatory actions. The aim of our study was to examine whether fisetin modulates inflammatory reaction in stimulated human mast cells (HMC-1). Fisetin decreased phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated gene expression and production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-4, IL-6, and IL-8 in HMC-1 cells. Fisetin inhibited PMACI-induced phosphorylation of p38 mitogen-activated protein kinase, extracellular-regulated kinase, and c-Jun N-terminal kinase. In addition, fisetin suppressed nuclear factor (NF)-kappaB activation induced by PMACI, leading to expression of IkappaB-alpha phosphorylation and degradation. Fisetin suppressed powerful induction of NF-kappaB promoter-mediated luciferase activity. These pharmacological actions of fisetin produce new suggestion that fisetin is a potential medicine for treatment of inflammatory diseases through the down-regulation of mast cell activation.
 ...
PMID:Anti-inflammatory activity of fisetin in human mast cells (HMC-1). 1707 62

Airway smooth muscle (ASM) cells can act as effector cells in the initiation and/or perpetuation of airway inflammation in asthma by producing various inflammatory chemokines or cytokines. Previous studies from our laboratory and others showed that the combination of tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) or endogenous IFNbeta results in a synergistic induction of various pro-inflammatory genes, including CD38 and regulated upon activation normal T-cell expressed and secreted (RANTES), in ASM cells. In contrast to these studies, we found that IFNgamma (1000 U/ml) markedly inhibited TNFalpha-induced expression of interleukin (IL)-6, IL-8, and eotaxin by 66.29+/-3.33, 43.86+/-7.11, and 63.25+/-6.46%, respectively. These genes were also found to be NF-kappaB-dependent in that TNFalpha-induced expression of IL-6, IL-8, and eotaxin was dose-dependently inhibited by the selective IKKbeta inhibitor 4-(2'-aminoethyl)amino-1,8-dimethylimidazo[1,2-a]quinoxaline (BMS-345541) (1-30 microM). Using a luciferase reporter construct containing kappaB sites, we found that IFNgamma (10-1000 U/ml) inhibits NF-kappaB-dependent gene transcription in a dose-dependent manner. Moreover, IFNgamma failed to affect TNFalpha-induced IkappaKbeta phosphorylation or IkappaB degradation as well as nuclear NF-kappaB/DNA interaction. It is noteworthy that IFNgamma decreases TNFalpha-induced histone acetyl transferase (HAT) and increases histone deacetylase (HDAC) activities. Finally, trichostatin A, an HDAC inhibitor, prevents IFNgamma inhibitory action on TNFalpha-induced gene expression. Together, our data indicate that IFNgamma is a potent inhibitor of specific TNFalpha-inducible inflammatory genes by acting on NF-kappaB transactivation via the modulation of HDAC function.
 ...
PMID:Inhibition of tumor necrosis factor-alpha-inducible inflammatory genes by interferon-gamma is associated with altered nuclear factor-kappaB transactivation and enhanced histone deacetylase activity. 1710 60

Scopoletin (6-methoxy-7-hydroxycoumarin) is a coumarin compound and a pharmacologically active agent that has been isolated from several plant species. However, as yet there is no clear explanation of how scopoletin affects the production of inflammatory cytokine. We therefore used cells from the human mast cell line (HMC-1) to investigate this effect. Scopoletin significantly and dose-dependently inhibits the way in which phorbol 12-myristate 13-acetate (PMA) plus A23187 induces the production of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 (P<0.05). The maximal rates at which scopoletin (0.2 mM) inhibited the production of TNF-alpha, IL-6, and IL-8 were 41.6%+/-4.2%, 71.9%+/-2.5%, and 43.0%+/-5.7%, respectively. In activated HMC-1 cells, the expression level of nuclear factor (NF)-kappaB/Rel A protein was increased in the nucleus whereas the level of NF-kappaB/Rel A in nucleus was decreased by treatment with scopoletin. Scopoletin decreased PMA plus A23187-induced luciferase activity. Scopoletin also inhibits IkappaBalpha phosphorylation and degradation in cytoplasm. These results indicate that scopoletin has a potential regulatory effect on inflammatory reactions that are mediated by mast cells.
 ...
PMID:Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1. 1711 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>