UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-8 (IL-8), a potent neutrophil chemotactic peptide that elicits pleiotropic biological effects is secreted in large amounts by normal human osteoblastic and bone marrow osteoprogenitor stromal (HBMS) cells in response to IL-1beta and tumor necrosis factor-alpha. In the present study we investigated the regulation of IL-8 gene expression by IL-1beta, osteotropic hormones, and protein kinase inhibitors in primary cultures of HBMS cells. The treatment of HBMS cells with IL-1beta increased the steady-state levels of IL-8 mRNA in a dose- and time-dependent fashion and was detectable within 1 h, reached maximal by 4 h, and remained elevated at 24 h, whereas parathyroid hormone (10(-7) and 10(-8) M) had no effect on IL-8 mRNA. Both synthetic and natural glucocorticoids dexamethasone (10(-7)-10(-10) M) and hydrocortisone (10(-6)-10(-8) M) inhibited IL-1beta-stimulated IL-8 mRNA expression. The suppressive effect of dexamethasone on IL-1beta-induced IL-8 mRNA was not observed in the presence of cycloheximide (5 microg/ml), indicating that the dexamethasone-mediated repression of IL-8 gene expression also depends on new protein synthesis. Experiments with actinomycin D demonstrated that IL-8 mRNA is long-lived and that glucocorticoids down-regulate IL-8 gene expression mainly by decreasing the mRNA stability in normal HBMS cells. Furthermore, as determined by nuclear run-on analysis, IL-1beta increased the rate of transcription of IL-8 gene and dexamethasone did not affect the IL-1beta-induced transcription of IL-8. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine, HCl (50 microM) and staurosporine (1 microM), potent inhibitors of protein kinase C, and genistein (100 microM), a specific protein tyrosine kinase inhibitor blocked IL-1beta-induced IL-8 gene expression. Because curcumin (20 microM), an inhibitor of c-jun/AP-1 and protein kinases, also blocked IL-1beta-stimulated IL-8 gene expression implicating c-JUN/AP-1 and protein phosphorylation in the induction of IL-8 gene expression by IL-1beta, we conclude that the regulation of IL-8 mRNA by IL-1beta is mediated via protein kinase-dependent signal transduction pathways. Our accumulated results have demonstrated that glucocorticoid suppression of IL-1beta-induced IL-8 mRNA occurs at the levels of post-transcription (mRNA stability) and protein synthesis.
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PMID:Regulation of interleukin-8 gene expression by interleukin-1beta, osteotropic hormones, and protein kinase inhibitors in normal human bone marrow stromal cells. 866 79

Interleukin (IL)-8, a prototypic human chemokine, was detected more than a decade ago as the founding member of the chemokine superfamily. One of the most remarkable properties of IL-8 is the variation of its expression levels. In healthy tissues, IL-8 is barely detectable, but it is rapidly induced by ten- to 100-fold in response to proinflammatory cytokines such as tumor necrosis factor or IL-1, bacterial or viral products, and cellular stress. Recently, significant advances in the understanding of signaling pathways, which coordinately regulate IL-8 transcription as well as mRNA stabilization in response to external stimuli, have been made. Maximal IL-8 amounts are generated by a combination of three different mechanisms: first, derepression of the gene promoter; second, transcriptional activation of the gene by nuclear factor-kappaB and JUN-N-terminal protein kinase pathways; and third, stabilization of the mRNA by the p38 mitogen-activated protein kinase pathway. In that way, cells are able to rapidly increase and at the same time, to fine-tune the amount of IL-8 secreted and thereby control the extent of leukocytes attracted to sites of tissue injury.
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PMID:Multiple control of interleukin-8 gene expression. 1242 6

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.
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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.
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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.
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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.
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PMID:A JNK-independent signaling pathway regulates TNF alpha-stimulated, c-Jun-driven FRA-1 protooncogene transcription in pulmonary epithelial cells. 1708 37

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.
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PMID:Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription. 1804 62

The role of Salmonella typhimurium type III secretion system (T3SS-1)-translocated proteins in chemokines' expression and protein phosphorylation was investigated in HeLa cells. Infection of HeLa cells with S. typhimurium activated IL-8 and GRO-alpha expression at higher levels than infection with a S. typhimurium sipAsopABDE2 mutant, confirming that T3SS-1-secreted proteins are required to fully induce chemokine expression in HeLa cells. A S. typhimurium sipAsopABDE2 mutant complemented with sipA or a strain carrying a chromosomal copy of sipA (sopABDE2 mutant) activated chemokines at significantly higher levels than a S. typhimurium sipAsopABDE2 mutant. However, extracellular addition of recombinant SipA failed to induce IL-8 expression. Phosphorylation analyses revealed that S. typhimurium induced a twofold increase in the phosphorylation of B23, CREB1, ERK1, JUN, p38MAPK, and NR1. JUN and p38MAPK were phosphorylated by S. typhimurium carrying a chromosomal copy of sipA (sopABDE2 mutant) while none was more than twofold phosphorylated in cells infected with the S. typhimurium sipAsopABDE2 mutant. Treating cells with JUN and p38MAPK inhibitors significantly decreased IL-8 expression in sopABDE2 mutant infected cells. These data indicate that S. typhimurium SipA induces expression of CXC chemokines through phosphorylation of IL-8-transcription regulatory proteins, JUN and p38MAK.
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PMID:Salmonella enterica Typhimurium SipA induces CXC-chemokine expression through p38MAPK and JUN pathways. 1911 19

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.
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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.
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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

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