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)

The present study was designed to investigate the capacity of human mononuclear phagocytes to produce a cytokine chemotactic for monocytes (monocyte chemotactic protein (MCP), alternative acronyms JE, monocyte chemotactic and activating factor, MCP-1, and tumor-derived chemotactic factor). Human PBMC exposed in vitro to bacterial LPS expressed high levels of MCP transcripts. Monocyte-depleted lymphoid cells were not induced to express MCP by LPS. Percoll-gradient purified monocytes were able to express high levels of MCP transcripts. In an effort to exclude a role of contaminating non-monocytic cells, mononuclear phagocytes were separated by flow cytometry and sorting: CD14+ cells exposed to LPS showed high levels of MCP mRNA. LPS-stimulated monocytes released chemotactic activity for monocytes that could be inhibited by absorption with anti-MCP antibodies. IL-1, TNF, IFN-gamma, granulocyte-macrophage-CSF and, to a lesser extent, macrophage-CSF, as well as inactivated streptococci, also induced MCP gene expression. Actinomycin D experiments indicated that induction of MCP in monocytes was gene transcription-dependent. The protein synthesis inhibitor cycloheximide (Cy) blocked IL-1-, TNF-, or LPS-induced MCP gene expression in monocytes. In contrast, expression of the structurally related chemotactic cytokine IL-8 was superinduced by Cy. Moreover, Cy superinduced MCP gene expression in cells other than monocytes, including endothelial cells, smooth muscle cell and fibrosarcoma cells, indicating different mechanisms of regulation in mononuclear phagocytes vs cells of other lineages. The capacity of cells of the monocyte-macrophage lineage to produce a cytokine that recruits and activates circulating monocytes may be of considerable importance in inflammatory and immunologic reactions. Thus, the mononuclear phagocyte system can autonomously regulate the extravasation and activation of immature elements of the same lineage, a key event in inflammation and immunity.
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PMID:Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. 137 May 16

A cDNA library was constructed from HL60 human promyelocyte poly(A)+ RNA harvested 3 h after induction of macrophage differentiation with 12-O-tetradecanoyl phorbol-13-acetate in the presence of cycloheximide. We isolated from this library a 1.6-kilobase full-length clone designated b4 whose corresponding mRNA was greatly increased in abundance in cytoplasmic RNA under these conditions. Dideoxy sequencing revealed that this mRNA encoded MONAP (monocyte-derived neutrophil-activating peptide), a 10-kilodalton monokine with neutrophil-specific chemotactic and enzyme-releasing activities. The 3' untranslated region of this mRNA was found to be 1.2 kilobases long and possessed nine copies of the AUUUA sequence known to be associated with regulation of mRNA stability. Actinomycin D chase experiments yielded evidence that cytoplasmic stabilization was one of the means of regulation of MONAP expression. Analysis of cytoplasmic poly(A)- RNA revealed the presence of several discrete truncated species that shared a common 5' end and appeared to be intermediates of degradation. S1 mapping showed that the 3' ends of these molecules were distributed throughout the 3' untranslated region, preferentially in A + U-rich regions, broadly correlating with the distribution of AUUUA sites. Nuclear run-on experiments indicated that transcriptional induction accounted for less than 15% of the accumulation of MONAP mRNA. This mRNA was induced in HL60 cells by treatment with several differentiation-inducing agents: 12-O-tetradecanoyl phorbol-13-myristate alone, sodium butyrate, vitamin D3, and dimethyl sulfoxide. It was also induced in quiescent diploid lung fibroblasts stimulated to divide by serum, and it was constitutively overexpressed by some human tumor lines.
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PMID:Regulation of the mRNA for monocyte-derived neutrophil-activating peptide in differentiating HL60 promyelocytes. 266 63

Lung cytokine production was examined after the intravenous administration of endotoxin to 23 normal human subjects. Bronchoalveolar lavage (BAL) was performed 7 days before and 1.5 or 5 h after endotoxin (4 ng/kg). Cytokine mRNA was evaluated in cell pellets (> 98% macrophages) by use of reverse transcription and the polymerase chain reaction. Immunoreactivity was measured by enzyme-linked immunosorbent assay of 20- to 40-fold concentrated BAL. Interleukin- (IL) 8 was detected in BAL (4-130 pg/ml) but not in the serum at baseline. Few neutrophils were found in BAL (< 1%) despite this IL-8 gradient. Peak serum IL-8 levels occurred 2 h after endotoxin (3,930 +/- 241 pg/ml), but BAL neutrophils and IL-8 did not increase. Peak serum tumor necrosis factor (TNF) levels occurred 1.5 h after endotoxin (1,844 +/- 210 pg/ml), but TNF was detected in only 1 of 20 BAL samples. TNF and IL-8 mRNA were detected by polymerase chain reaction in > 70% of the BAL samples before endotoxin, whereas IL-1 alpha, IL-1 beta, and IL-6 were detected in < 25% of the BAL samples. After endotoxin, no change was detected in cytokine mRNA expression. Actinomycin D treatment of the BAL did not alter the pattern of cytokine mRNA expression. These data suggest that mechanisms exist to insulate the alveolar space from the stimulatory effects of endotoxin and high circulating levels of cytokines. Additional factors appear to control the chemotactic effects of IL-8 on neutrophils in the air spaces during acute systemic inflammation.
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PMID:Compartmentalization of the acute cytokine response in humans after intravenous endotoxin administration. 836 3

Fibroblasts play an indirect augmenting effector role in the inflammatory response by releasing growth and differentiation factors and other inflammatory mediators after activation by inflammatory cytokines such as interleukin (IL)-1, but whether direct activation occurs by exogenous agents such as endotoxin (lipopolysaccharide, LPS) remains controversial. Using a number of primary human airways tissue-derived fibroblast lines, we demonstrate that in contrast to IL-1 alpha, LPS significantly induced gene expression and production of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-8, and IL-6 only in nasal but not bronchial or lung tissue-derived fibroblasts. Enhanced expression was dose- and time-dependent, and the minimal stimulatory dose was 10 ng LPS/ml. Polymyxin B entirely abrogated increased cytokine expression by LPS. Actinomycin D treatment largely inhibited expression, and LPS markedly increased an IL-6 gene promoter-driven luciferase reporter response in transfected nasal fibroblasts, suggesting enhanced expression may involve transcriptional regulation. Secondary protein or IL-1 synthesis requirement seemed unlikely since cycloheximide superinduced LPS-stimulated cytokine expression and anti-IL-1 alpha/beta antibodies failed to abrogate the response. Thus our data show that GM-CSF, IL-8, and IL-6 are directly inducible in nasal fibroblasts by LPS, and establish heterogeneous responsiveness to LPS by different fibroblast populations in the airways.
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PMID:Lipopolysaccharide induces expression of granulocyte/macrophage colony-stimulating factor, interleukin-8, and interleukin-6 in human nasal, but not lung, fibroblasts: evidence for heterogeneity within the respiratory tract. 839 62

Expression of DAF (CD55) is enhanced on colonic epithelial cells of patients with ulcerative colitis (UC), and stool DAF concentrations are increased in patients with active disease. Cytokines are known to modulate DAF expression in various human cells, and lesions of UC reveal altered profiles of cytokine production. In this study, we evaluate the effects of various cytokines, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, and interferon-gamma (IFN-gamma), on the synthesis and kinetics of DAF protein in HT-29 human intestinal epithelial cells. Using flow cytometry and an ELISA, we found that HT-29 cells constitutively express DAF on the cell surface and spontaneously release DAF into the culture supernatant under standard culture conditions. When the culture supernatant was centrifuged at 100000g, nearly a half of DAF was precipitated, indicating that one half of the released DAF was present as a membrane-bound form and the other half as a soluble form. Analysis of the culture supernatant of biotin surface-labelled HT-29 cells suggested that the soluble form DAF was derived by secretion from within the cell or by cleavage from the cell surface. Among the cytokines, IL-4 markedly, and IL-1beta moderately, enhanced the expression and the release of DAF. Actinomycin D, cycloheximide, and brefeldin A inhibited the increase in DAF release induced by IL-4 and IL-1beta stimulation. These results suggest that DAF is released from intestinal epithelial cells in response to cytokine stimulation and that IL-4 and IL-1beta are possible cytokines involved in DAF release into the colonic lumen of patients with UC.
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PMID:Cytokine-stimulated release of decay-accelerating factor (DAF;CD55) from HT-29 human intestinal epithelial cells. 973 66

Interleukin (IL) 12 is a heterodimeric cytokine mainly produced by phagocytes-important target cells for IL-12 in particular with a chemotactic effect-and antigen-presenting cells in response to various microorganisms. Because IL-8 is a strong chemokine for polymorphonuclear neutrophils (PMNs), we investigated the effect of IL-12 on PMN IL-8 production. IL-12 alone had no significant effect, but with lipopolysaccharide (LPS) it was additive at both protein and mRNA levels. Actinomycin D at the beginning of culture inhibited IL-8 mRNA induction, whereas late addition affected IL-8 transcript stability, suggesting gene transcription involvement. Results with parthenolide and tyrphostin AG490 suggest that nuclear factor-kappaB and signal transducer and activator of transcription 4 play a role. The IL-12 additive effect was restricted to IL-8 release, with no action on cell-associated IL-8. IL-12 additive effects occurred after 18 h of culture, with no marked up-regulation of IL-12 receptor expression, and were blocked by actinomycin D added after 16 h of culture. Tumor necrosis factor (TNF) alpha and interferon (IFN) gamma had intermediate roles; their specific inhibition reduced IL-12's effect. IL-12's chemotactic mechanism seemed mediated by overproduction and release of IL-8 by human PMNs in the presence of LPS, an effect involving TNF-alpha and IFN-gamma secretion. These results point to a new role for IL-12 in inflammation, through an autocrine amplification loop.
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PMID:Interleukin-12 increases interleukin 8 production and release by human polymorphonuclear neutrophils. 1152 94

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) upregulates a spectrum of inflammatory cytokines and adhesion molecules different from those induced by classic inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide. Interestingly, Ox-PAPC also induces the expression of a set of proteins similar to those induced by TNF-alpha or lipopolysaccharide, which include the chemokines monocyte chemotactic protein-1 (MCP-1) and interleukin (IL)-8. To elucidate the molecular mechanisms of Ox-PAPC-induced gene expression and to determine whether Ox-PAPC and other inflammatory mediators such as TNF-alpha utilize common signaling pathways, we examined the transcriptional regulation of IL-8 by Ox-PAPC and TNF-alpha in human aortic endothelial cells. Both Ox-PAPC and TNF-alpha induced the expression of IL-8 mRNA in a dose-dependent fashion; however, the kinetics of IL-8 mRNA accumulation between the 2 ligands differed. Ox-PAPC-induced IL-8 mRNA was seen as early as 30 minutes, peaked between 4 and 8 hours, and decreased substantially by 24 hours. In contrast, TNF-alpha-induced IL-8 mRNA synthesis was elevated at 30 minutes, peaked at 2 hours, and reached basal/undetectable levels by 6 hours. Actinomycin D experiments suggested that both Ox-PAPC and TNF-alpha regulate the expression of IL-8 at the transcriptional level. Furthermore, the half-life of IL-8 mRNA for both ligands was similar (<30 minutes), suggesting that mRNA stability was not responsible for the differences in the kinetics of IL-8 accumulation between the 2 ligands. Transient transfection studies with reporter constructs containing 1.48 kb of the IL-8 promoter identified an Ox-PAPC-specific response region between -133 and -1481 bp of the IL-8 promoter. In contrast, TNF-alpha activation of the IL-8 promoter was mediated almost entirely through the nuclear factor-kappaB and activation protein-1 response elements present between -70 and -133 bp of the IL-8 promoter. Thus, although Ox-PAPC and TNF-alpha both induced IL-8 synthesis, our data suggest that the 2 ligands utilize different mechanisms in the regulation of IL-8 transcription.
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PMID:Increased transcription of IL-8 in endothelial cells is differentially regulated by TNF-alpha and oxidized phospholipids. 1159 30

Zinc plays an important role in cell-mediated immune function. Altered cellular immune response resulting from zinc deficiency leads to frequent microbial infections, thymic atrophy, decreased natural killer activity, decreased thymic hormone activity, and altered cytokine production. In this study, we examined the effect of zinc deficiency on IL-2 and IFN-gamma in HUT-78 (Th0) and D1.1 (Th1) cell lines and TNF-alpha, IL-1 beta, and IL-8 in the HL-60 (monocyte-macrophage) cell line. The results demonstrate that zinc deficiency decreased the levels of IL-2 and IFN-gamma cytokines and mRNAs in HUT-78 after 6 h of PMA/p-phytohemagglutinin (PHA) stimulation and in D1.1 cells after 6 h of PHA/ionomycin stimulation compared with the zinc-sufficient cells. However, zinc deficiency increased the levels of TNF-alpha, IL-1 beta, and IL-8 cytokines and mRNAs in HL-60 cells after 6 h of PMA stimulation compared with zinc-sufficient cells. Actinomycin D study suggests that the changes in the levels of these cytokine mRNAs were not the result of the stability affected by zinc but might be the result of altered expression of these cytokine genes. These data demonstrate that zinc mediates positively the gene expression of IL-2 and IFN-gamma in the Th1 cell line and negatively TNF-alpha, IL-1 beta, and IL-8 in the monocyte-macrophage cell line. Our study shows that the effect of zinc on gene expression and production of cytokines is cell lineage specific.
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PMID:Zinc modulates mRNA levels of cytokines. 1281 20

Pancreatic carcinoma is one of the most lethal of the gastrointestinal malignant tumors. Chronic inflammation leads to cancer development and progression. Interleukin-8 (CXCL-8) is a CXC chemokine, which plays an important role in neutrophil chemotaxis and activation. We previously reported that CXCL-8 was produced by a variety of human carcinoma cells and tissues, and that CXCL-8 promoted proliferation in pancreatic carcinoma cells (SUIT-2). In the present study, we analyzed whether various cytokines affect cell proliferation by CXCL-8 expression in pancreas carcinoma cells. All examined pancreatic carcinoma cells expressed CXCL-8 and TNFRII mRNA constitutively in RPMI-1640 medium without FBS. TNF-alpha, LIF, IL-1beta, IL-6, IL-8, or IFN-beta enhanced the expression of CXCL-8 mRNA, but IL-10 did not in Hs-700T cells. Actinomycin D suppressed and cycloheximide augmented CXCL-8 mRNA which was induced by TNF-alpha or not. The half-life of CXCL-8 mRNA was 36.5 min by TNF-alpha and 35.2 min by no stimulation. In our previous study, LIF promoted cell growth in Hs-700T cells. LIF induced CXCL-8 mRNA in a dose- and time-dependent manner. Addition of recombinant CXCL-8 did not induce cell growth of Hs-700T. Anti-CXCL-8 IgG significantly suppressed cell growth. CXCL-8 would act as an autocrine growth factor in Hs-700T cells, which expressed CXCL-8 mRNA highly without stimulation. Curcumin (diferuloylmethane), NF-kappaB inhibitor, suppressed cell proliferation in Hs-700T cells. These results suggest that CXCL-8 plays a pivotal role in progression of pancreatic cancer, and its expression is influenced by inflammatory cytokines in pancreatic tumor microenvironment.
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PMID:Induction of interleukin-8 (CXCL-8) by tumor necrosis factor-alpha and leukemia inhibitory factor in pancreatic carcinoma cells: Impact of CXCL-8 as an autocrine growth factor. 1767 91

While much is known about the deleterious effects of pro-inflammatory cytokines on development of vascular disease, little is reported on the direct effects of anti-inflammatory cytokines on the vascular smooth muscle cell (VSMC) response to injury. Interleukin-19 (IL-19) is a recently described Th2, anti-inflammatory interleukin. We have previously reported that IL-19 is absent in normal VSMC, but induced in VSMC by inflammatory cytokines and in arteries by injury. IL-19 is anti-proliferative for VSMC. The purpose of this study is to determine the molecular mechanism of these effects. In cultured, primary human VSMC, IL-19 reduces abundance of proliferative and inflammatory gene proteins and mRNA, including Cyclin D1, IL-1beta, IL-8, and COX2. IL-19 does not inhibit NF-kappaB, but does transiently reduce cytoplasmic abundance of the mRNA stability factor HuR. The mRNA stabilizing function of HuR is linked to its phosphorylation and cytoplasmic translocation. IL-19 reduces serine phosphorylation of HuR, and activation of PKCalpha, a known regulator of HuR translocation. Actinomycin D transcription blockade demonstrates that IL-19 treatment significantly reduces stability of proliferative and inflammatory mRNAs. Knock down of HuR with siRNA also reduces stability of these inflammatory mRNA transcripts. These data indicate that IL-19 has direct effects on VSMC mRNA stability. One potential mechanism whereby IL-19 reduces the VSMC response to injury is by regulation of HuR abundance and cytoplasmic translocation, with a subsequent decrease in mRNA half-life of proliferative and inflammatory mRNA transcripts.
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PMID:Il-19 reduces VSMC activation by regulation of mRNA regulatory factor HuR and reduction of mRNA stability. 2045 30


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