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 this study, the effect of naphthalene on the induction of apoptosis and gene expression profiles in cord blood cells has been evaluated, as well as its activity on the BCL-2 related protein expression. After 6, 24, and 48 h of exposure to naphthalene (500 microM), a decrease in cell death was observed: the cells became more resistant to the toxicant and capable of surviving after the treatment. A Western blot analysis revealed an overexpression of BCL-2, c-JUN, c-FOS, and RAF-1 proteins, which are involved in the antiapoptotic response and in the regulation of cell growth, differentiation, and development. Furthermore, macroarray analysis showed that naphthalene modified cord blood gene expression, inducing IL-8 precursor and T-cell transcription factor and decreasing the level of RNA-binding protein FUS/TLS.
 ...
PMID:Naphthalene exposure: effects on gene expression and proliferation in human cord blood cells. 1459 51

Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1microM. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NF(kappa)B and AP-1 transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNFalpha-induced phosphorylation and proteosomal destruction of I(kappa)B(alpha). Inasmuch as I(kappa)B(alpha) is the principal inhibitor of the NF(kappa)B signaling pathway, preservation of intact I(kappa)B(alpha) would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNF(alpha)-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP-1 site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NF(kappa)B and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low muM concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung.
 ...
PMID:Amphiphilic pyridinium salts block TNF alpha/NF kappa B signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells. 1596 54

The neuropeptide S (NPS)-NPS receptor 1 (NPSR1) pathway has recently been implicated in the pathogenesis of asthma. The purpose of this study was to identify downstream gene targets regulated by NPSR1 upon NPS stimulation. A total of 104 genes were found significantly up-regulated and 42 down-regulated by microarray analysis 6 h after NPS administration. By Gene Ontology enrichment analysis, the categories 'cell proliferation', 'morphogenesis' and 'immune response' were among the most altered. A TMM microarray database comparison suggested a common co-regulated pathway, which includes JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members and dual specificity phosphatases. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), exhibited a significant NPS dose-response relationship as confirmed by quantitative reverse-transcriptase-PCR and for MMP10 by immunoassay. Immunohistochemical analyses revealed that MMP10 and TIMP metallopeptidase inhibitor 3 (TIMP3) were both strongly expressed in bronchial epithelium, and macrophages and eosinophils expressed MMP10 in asthmatic sputum samples. Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS-NPSR1 signaling may be of relevance in the pathogenesis of asthma.
 ...
PMID:Downstream target genes of the neuropeptide S-NPSR1 pathway. 1692 87

Among the several effectors that mediate TNF-alpha action is AP-1, which consists of transcription factors belonging to the JUN and FOS families. Although the effects of TNF-alpha in immune cells, such as the induction of NF-kappaBeta, are well known, the mechanisms by which it induces transcriptional activation of AP-1 in pulmonary epithelial cells are not well defined. In this study, we report that TNF-alpha stimulates the expression of the FRA-1 protooncogene in human pulmonary epithelial cells using c-Jun, acting via a 12-O-tetradecanoylphorbol-13 acetate response element located at -318. Although TNF-alpha stimulates phosphorylation of c-Jun, the inhibition of JNK activity had no significant effect on FRA-1 induction. Consistent with this result, ectopic expression of a c-Jun mutant lacking JNK phosphorylation sites had no effect on the TNF-alpha-induced expression of the promoter. In contrast, inhibition of the ERK pathway or ectopic expression of an ERK1 mutant strikingly reduced FRA-1 transcription. ERK inhibition not only blocked phosphorylation of Elk1, CREB, and ATF1, which constitutively bind to the FRA-1 promoter, but also suppressed the recruitment of c-Jun to the promoter. We found that short interfering RNA-mediated silencing of FRA-1 enhances TNF-alpha-induced IL-8 expression, whereas overexpression causes an opposite effect. Our findings collectively indicate that ERK signaling plays key roles in both Elk1, CREB, and ATF-1 activation and the subsequent recruitment of c-Jun to the FRA-1 promoter in response to TNF-alpha in pulmonary epithelial cells.
 ...
PMID:A JNK-independent signaling pathway regulates TNF alpha-stimulated, c-Jun-driven FRA-1 protooncogene transcription in pulmonary epithelial cells. 1708 37

Infection of the human host by Streptococcus pneumoniae begins with colonization of the nasopharynx, which is mediated by the adherence of bacteria to the respiratory epithelium. Several studies have indicated an important role for the pneumococcal capsule in this process. Here, we used microarrays to characterize the in vitro transcriptional response of human pharyngeal epithelial Detroit 562 cells to the adherence of serotype 2 encapsulated strain D39, serotype 19F encapsulated strain G54, serotype 4 encapsulated strain TIGR4, and their nonencapsulated derivatives (Deltacps). In total, 322 genes were found to be upregulated in response to adherent pneumococci. Twenty-two genes were commonly induced, including those encoding several cytokines (e.g., interleukin 1beta [IL-1beta] and IL-6), chemokines (e.g., IL-8 and CXCL1/2), and transcriptional regulators (e.g., FOS), consistent with an innate immune response mediated by Toll-like receptor signaling. Interestingly, 85% of genes were induced specifically by one or more encapsulated strains, suggestive of a capsule-dependent response. Importantly, purified capsular polysaccharides alone had no effect. Over a third of these loci encoded products predicted to be involved in transcriptional regulation and signal transduction, in particular mitogen-activated protein kinase signaling pathways. Real-time PCR of a subset of 10 genes confirmed the microarray data and showed a time-dependent upregulation of, especially, innate immunity genes. The downregulation of epithelial genes was most pronounced upon adherence of D39Deltacps, as 68% of the 161 genes identified were repressed only by this nonencapsulated strain. In conclusion, we identified a subset of host genes specifically induced by encapsulated strains during in vitro adherence and have demonstrated the complexity of interactions occurring during the initial stages of pneumococcal infection.
 ...
PMID:Analysis of the in vitro transcriptional response of human pharyngeal epithelial cells to adherent Streptococcus pneumoniae: evidence for a distinct response to encapsulated strains. 1770 18

Cysteinyl-leukotrienes are involved in inflammation and act on at least two G-protein-coupled receptors, CysLT1 and CysLT2. However, the role of the CysLT2 receptor as well as its signaling remain poorly understood. Here we show that leukotriene (LT)C(4) induced the production of the chemokine interleukin (IL)-8 in endothelial cells. To further study the signaling cascade involved, HEK293 cells were stably transfected with CysLT2 and used to study the transcriptional regulation of the IL-8 promoter. Stimulation of the cells with increasing concentrations of LTC(4) resulted in a time- and concentration-dependent induction of IL-8 transcription and protein synthesis. Use of IL-8 promoter mutants with substitutions in their NF-kappaB, AP-1, or NF-IL-6 binding elements revealed an almost total requirement for NF-kappaB and AP-1 elements, and a lesser requirement for the NF-IL-6 element. Overexpression of dominant-negative IkappaBalpha prevented the IL-8 transactivation induced by LTC(4). LTC(4) stimulation induced NF-kappaB and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN.c-FOS complex, respectively. Transfection of the cells with a dominant negative (dn) form of PKCepsilon prevented p65 phosphorylation, whereas dnPKCdelta prevented AP-1 binding. Moreover, dnPKCdelta, dnPKCepsilon, and dnPKCzeta prevented LTC(4)-induced IL-8 transcription in response to LTC(4). Our data show for the first time that LTC(4) can act via the CysLT2 receptor to transcriptionally activate chemokine production through induction of NF-kappaB and AP-1 transcription factors. These findings suggest the potential implication of CysLT2 in the inflammatory response through the modulation of chemokine gene transcription.
 ...
PMID:Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription. 1804 62

Curcumin, a natural product isolated from the plant Curcuma longa, has a diverse range of molecular targets that influence numerous biochemical and molecular cascades. Curcumin has been shown to inhibit nuclear factor kappaB (NF-kappaB) activation at several steps in the NF-kappaB signaling pathways and thereby controls numerous NF-kappaB-regulated genes involved in various diseases. In the present study, we investigated the effect of curcumin pretreatment on 84 tumor necrosis factor-alpha (TNF-alpha)-activated genes of NF-kappaB pathways in K562 cells, using a real-time PCR array. Our results show that transcription of 29 NF-kappaB-related mRNAs was significantly downregulated (CARD4, CCL2, CD40, CSF2, F2R, ICAM1, IKBKB, IKBKE, IL1A, IL1B, IL6, IL8, IRAK2, MALT1, MAP3K1, MYD88, NFKB1, NFKB2, NFKBIA, PPM1A, RAF1, RELB, STAT1, TLR3, TNF, TNFalphaIP3, TNFSF10, and TICAM1), whereas 10 mRNAs were induced (AGT, CASP1, CSF3, FOS, IFNG, IL10, TICAM2, TLR2, TLR9, and TNFRSF7). Western blot analysis of CD40, NFKB1 (p50), RELB, NFKBIA (IkappaBalpha), and IL10 as well as an IL8 secretion assay confirmed our results. Taken together, we show that curcumin regulates an impressive number of NF-kappaB genes within the different NF-kappaB signaling pathways.
 ...
PMID:Effect of curcumin on nuclear factor kappaB signaling pathways in human chronic myelogenous K562 leukemia cells. 1972 87

The gastrointestinal inflammatory response may play a role in the susceptibility of preterm infants for infections. We previously reported a trend toward lower endogenous infection morbidity after enteral supplementation of neutral and acidic oligosaccharides (SC GOS/LC FOS/AOS). We hypothesize that enteral supplementation of prebiotics may decrease infectious morbidity by reducing intestinal inflammation. Therefore, we aimed to determine the effect of enteral supplementation of prebiotics on intestinal inflammation, as measured by fecal IL-8 (f-IL-8) and calprotectin (f-calprotectin), in preterm infants. In a randomized controlled trial, infants with a GA <32 wk and/or birth weight <1,500 g received enteral supplementation of prebiotics or placebo (maltodextrin) between d 3 and 30 of life. F-IL-8 and f-calprotectin was assessed at baseline, d 7, 14, and 30 of life. In total, 113 infants were included. Baseline patient and nutritional characteristics were not different in the SC GOS/LC FOS/AOS (n = 55) and the placebo group (n = 58). Enteral supplementation of prebiotics had no effect on f-IL-8 and f-calprotectin. F-IL-8 and f-calprotectin were strongly correlated at all time points (p < 0.001). In conclusion, enteral supplementation of prebiotics (SC GOS/LC FOS/AOS) does not affect f-IL-8 and f-calprotectin levels in preterm infants.
 ...
PMID:Effect of neutral and acidic oligosaccharides on fecal IL-8 and fecal calprotectin in preterm infants. 2122 32

Natural luteolysis involves multiple pulses of prostaglandin F2alpha (PGF) released by the nonpregnant uterus. This study investigated expression of 18 genes from five distinct pathways, following multiple low-dose pulses of PGF. Cows on Day 9 of the estrous cycle received four intrauterine infusions of 0.25 ml of phosphate-buffered saline (PBS) or PGF (0.5 mg of PGF in 0.25 ml of PBS) at 6-h intervals. A luteal biopsy sample was collected 30 min after each PBS or PGF infusion. There were four treatment groups: Control (n = 5; 4 PBS infusions), 4XPGF (4 PGF infusions; n = 5), 2XPGF-non-regressed (2 PGF infusions; n = 5; PGF-PBS-PGF-PBS; no regression after treatments), and 2XPGF-regressed (PGF-PBS-PGF-PBS; regression after treatments; n = 5). As expected, the first PGF pulse increased mRNA for the immediate early genes JUN, FOS, NR4A1, and EGR1 but unexpectedly also increased mRNA for steroidogenic (STAR) and angiogenic (VEGFA) pathways. The second PGF pulse induced immediate early genes and genes related to immune system activation (IL1B, FAS, FASLG, IL8). However, mRNA for VEGFA and STAR were decreased by the second PGF infusion. After the third and fourth PGF pulses, a distinctly luteolytic pattern of gene expression was evident, with inhibition of steroidogenic and angiogenic pathways, whereas, there was induction of pathways for immune system activation and production of PGF. The pattern of PGF-induced gene expression was similar in corpus luteum not destined for luteolysis (2X-non-regressed) after the first PGF pulse but was very distinct after the second PGF pulse. Thus, although the initial PGF pulse induced mRNA for many pathways, the second and later pulses of PGF appear to have set the distinct pattern of gene expression that result in luteolysis.
 ...
PMID:Patterns of gene expression in the bovine corpus luteum following repeated intrauterine infusions of low doses of prostaglandin F2alpha. 2232 31

Trivalent inorganic arsenite [iAs(III)] is known to alter the expression of a number of genes associated with transcription and cell proliferation, which was thought to be one of the possible mechanisms of arsenical carcinogenesis. However, the detailed mechanisms underlying iAs(III) induction of changes in gene expression are not fully understood. Here we examine the role of histone H3 phosphorylation at serine 10 (Ser(10) ) in gene regulation when the cells were treated with iAs(III). Among the 34 genes tested, iAs(III) induced mRNA expression of JUN, FOS, EGR1, HMOX1, HSPA1A, IL8, GADD45A, GADD45B and GADD153. Phosphorylation of histone H3 Ser(10) was induced by iAs(III) in interphase cells, and was effectively blocked by the ERKs pathway inhibitor (U0126). U0126 treatment significantly reduced constitutive mRNA expression of FOS and EGR1, and dramatically suppressed the induction of FOS, EGR1 and IL8 mRNA in iAs(III)-treated cells. The other genes, which were induced by iAs(III), were not affected by U0126 treatment. When the histone H3 nonphosphorylatable mutant of serine 10 (S10A) was overexpressed in cells, iAs(III) induction of FOS, EGR1and IL8 expression was significantly decreased as compared with wild-type cells. The other genes induced by iAs(III) were not changed in S10A cells nor by U0126 treatment. In addition, S10A cells were more resistant to iAs(III) cytotoxicity. These results indicated that the phosphorylation of histone H3 at Ser(10) through the ERKs pathway in interphase cells is an important regulatory event for iAs(III)-mediated gene expression. Aberrant gene expression seems to be an important cause of cytotoxicity and may have some relation to iAs(III) carcinogenicity.
 ...
PMID:Phosphorylation of histone H3 at serine 10 has an essential role in arsenite-induced expression of FOS, EGR1 and IL8 mRNA in cultured human cell lines. 2235 77


1 2 3 4 Next >>