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)

Previously we have isolated about 60 novel cDNA clones whose corresponding mRNAs are induced by mitogenic activation in human peripheral blood T cells. Here we describe the primary structure and regulation of two such cloned genes, pAT 464 and pAT 744, which may encode new lymphokines/cytokines. Similar to IL-2, both genes require the synergy of agents such as PHA and PMA for optimal expression, and, in addition, the induction of both is sensitive to the immunosuppressive drug cyclosporin A. The two genes can be expressed in T cells, B cells, and the promyelocytic cell line HL60, but they are not expressed in human fibroblasts, suggesting that their expression is restricted to hematopoietic lineages. The predicted peptides encoded by these two clones feature hydrophobic N-terminal leaders characteristic of secreted proteins. The predicted size of both proteins is about 8 kDa upon cleavage of the putative leader peptide. pAT 464 and pAT 744 are very similar to each other and also share some critical amino acid similarity with a newly emerging family of secreted factors including connective tissue activating factor III, platelet factor 4, an IFN-gamma-induced factor, macrophage inflammatory protein, and a factor chemotactic to neutrophils (3-10C, monocyte-derived neutrophil chemotactic factor, neutrophil-activating factor). Some of these factors have been shown to display functions associated with an inflammatory response and/or have mitogenic activities. Collectively, the data presented here suggest that pAT 464 and pAT 744 encode novel lymphokines/cytokines which may play roles during an immune response similar to those enacted by these structurally related factors.
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PMID:Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors. 252 82

To identify possible regulatory sites of the gene expression, we cloned the genomic DNA of human monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8), whose mRNA is induced by IL-1 or TNF and determined its entire nucleotide sequence. The results show that the MDNCF/IL-8 gene consists of 4 exons and 3 introns with a single "CAT"- and "TATA"-like structure. The 5'-flanking region of MDNCF/IL-8 gene shows no overall sequence similarity with that of other cytokine and acute phase reactant genes whose production is also affected by IL-1 and TNF. The 5' flanking region, however, contains potential binding sites for several nuclear factors including activation factor-1, activation factor-2, IFN regulatory factor-1, and hepatocyte nuclear factor-1. In addition, the glucocorticoid responsive element and heat shock element were located in the 5'-flanking region. Inasmuch as PMA induces MDNCF/IL-8 mRNA accumulation in human PBMC and a glucocorticoid inhibits the induction of MDNCF/IL-8 mRNA by LPS, the expression of this gene is probably regulated by interaction of these nuclear factors with the 5'-flanking DNA.
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PMID:Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8. 266 93

Lysophosphatidylcholine (lyso-PC) is a major phospholipid component of atherogenic lipoproteins (e.g., oxidized LDL and beta-VLDL) and also can be generated through the action of leukocyte-secreted phospholipase A2 at sites of inflammation. We have previously reported that lyso-PC can activate cultured endothelia, resulting in the selective upregulation of adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. In this study, we have found that lyso-PC increased steady state mRNA levels for two smooth muscle/fibroblast-directed growth factors, the A and B chains of PDGF and heparin-binding EGF-like protein (HB-EGF), in cultured human endothelial cells. Lyso-PC did not upregulate the expression of certain other inducible endothelial genes, including E-selectin, IL-8, or monocyte chemoattractant protein-1 in the same cells, in contrast to the coordinate pattern of activation typically observed with other stimuli, such as TNF alpha, bacterial endotoxin, or PMA. Nuclear runoff assays documented an increased transcriptional rate for the HB-EGF gene in lyso-PC-treated cells. Northern blot analyses, after actinomycin D treatment, further indicated that the increased amounts of mRNA for HB-EGF, PDGF A and B chains, and intercellular adhesion molecule-1 were not dependent upon message stabilization. We conclude that lyso-PC can induce growth factor gene expression in cultured endothelial cells and thus may contribute to the migration and proliferation of smooth muscle cells and fibroblasts in various response-to-injury settings in vivo.
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PMID:Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. 750 51

CD43, an anionic rod-like mucin molecule on white blood cells, is thought to provide a barrier that prevents interactions of other surface molecules and acts as negative regulator of cell function. As a correlate, CD43 is expected to be altered or down-regulated when blood cells are functionally activated. This study examines CD43 of blood neutrophils before and after treatment with known activating agents. Flow cytometry indicated that PMA and A23187, and to a much lesser extent, FMLP and IL-8, decrease neutrophil expression of CD43. Two separate mechanisms were identified for CD43 down-regulation. Both are proteolytic processes. PMA-induced down-regulation is a rapid process involving proteolysis at a minimum of two sites, one within the N-terminal distal region recognized by mAbs and the other at a membrane-proximal site. The PMA-induced protease, cd43' ase, is characterized by insensitivity to DFP, TLCK, leupeptin, pepstatin, and 1,10 phenanthroline (< 5 mM). PMA-induced CD43 down-regulation is extensive but never complete, terminating at approximately 10 min after down-regulating 65 to 85% of molecules, and thereby converting neutrophils from dense to sparse CD43 expression. The second CD43 down-regulation mechanism, although likely a regulated event in vivo, occurred slowly in this study in neutrophils incubated without additives; the process is not affected by PMA, involves the action of a DFP-sensitive protease, releases N-terminal mAb-reactive fragments of 52 kDa or 40 kDa and can be mimicked by exogenous neutrophil elastase. The complexity and apparent tight regulation described here for the two down-regulatory mechanisms are consistent with an important role for CD43 in preventing or dampening cell surface interactions of blood neutrophils.
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PMID:Two proteolytic pathways for down-regulation of the barrier molecule CD43 of human neutrophils. 751 53

Three highly homologous serine protease inhibitors, SPI-1, SPI-2 and SPI-3 (contrapsins), are synthesized in rat liver. Their expression is regulated differently in healthy and inflamed animals. We found that interleukin 6 (IL-6), a major acute phase cytokine, and to a lesser extent leukemia inhibitory factor (LIF), both together with glucocorticoids, are responsible for the regulation of expression of the contrapsins in rat hepatocytes in primary culture. The effect of IL-6 is time- and dose-dependent. IL-1, TGF beta 1, HGF, PMA and IL-8 did not have any effect on contrapsin mRNA levels. We postulate that SPI-1, SPI-2 and SPI-3 belong to the class II acute phase proteins. Additionally, we show induction of SPI-3 mRNA in rat liver by in situ hybridization using a specific oligonucleotide probe.
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PMID:Rat contrapsins are the type II acute phase proteins: regulation by interleukin 6 on the mRNA level. 751 32

The capacity of renal epithelial cells to produce IL-6, IL-8 and TNF was investigated. Cultures of explanted human renal cortical epithelial cells (RCEC) were established, and cytokine-release and mRNA expression by these cells were measured. IL-6, IL-8 and TNF release were measured after stimulation with IL-1 beta TNF-alpha, LPS and the phorbol esther PMA. All these agents were found to induce increased release of the three cytokines. Whilst no spontaneous TNF-release occurred, IL-6 and IL-8 were continuously released by non-stimulated RCEC cultures. IL-1 beta was the most potent trigger, enhancing both RCEC cytokine release and expression of IL-6, IL-8 and TNF mRNA. Indomethacin, budesonide, cyclosporin and FK 506 were tested for their influence on RCEC cytokine release. Only the steroid budesonide appeared to reduce both spontaneous and IL-1 beta induced cytokine release. Our data demonstrate stimulus specific release of IL-6, IL-8 and TNF by RCEC, and suggest that cytokine cell-to-cell communication may be important in regulating inflammatory processes in the kidney.
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PMID:IL-6, IL-8 and TNF production by cytokine and lipopolysaccharide-stimulated human renal cortical epithelial cells in vitro. 752 16

TNF is a strong secretagogue for surface-contacting neutrophils. During inflammation, endothelium offers the first substrate for neutrophil adherence and for modulation of the toxic response of neutrophils to soluble agonists such as TNF. In this in vitro study, evidence is presented that endothelium participates actively in TNF-induced neutrophil respiratory burst activity by expressing platelet-activating factor (PAF) in response to initial neutrophil H2O2 release. Three findings are shown that favor such a mechanism. First, PAF receptor antagonists reduced H2O2 release by TNF-activated neutrophils placed on endothelium approximately by 50%, whereas H2O2 responses by neutrophils placed on serum-coated polystyrene remained intact. Second, preincubation of HUVEC with known PAF-inducing agents PMA, H2O2, and thrombin, followed by fixation, enhanced neutrophil H2O2 release in response to TNF. H2O2 release by these neutrophils was sensitive to the presence of PAF receptor antagonists, whereas H2O2-release from neutrophils placed on fixed nonactivated endothelial cells was not. Finally, replacing endothelium by monolayers of human renal cortical epithelial cells and human fibroblasts, cells that are known to produce less PAF than endothelial cells, reduced the effect of PAF receptor antagonists. P-selectin expression and IL-8 release, two other ways by which endothelial cells might influence H2O2-release by TNF preincubated neutrophils, were examined in parallel, and were found not to influence TNF-induced neutrophil H2O2-release. We conclude that during neutrophil-endothelial interaction in inflammation, endothelium modulates the toxic response of neutrophils to TNF. Endothelial cell-associated PAF, but not endothelial cell IL-8 release and P-selectin expression, is likely to participate in TNF-induced neutrophil respiratory burst activity.
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PMID:Endothelial cell associated platelet-activating factor (PAF), a costimulatory intermediate in TNF-alpha-induced H2O2 release by adherent neutrophil leukocytes. 752 2

We established an improved non-radioactive in situ hybridization (ISH) method to detect mRNA of cytokines in cell preparations and tissues. Via this method we could demonstrate various cytokines in stimulated peripheral blood mononuclear cells (PBMC), lymphoid cell lines and human lymphoid tissues. The probes for the in situ hybridization were made by labelling cytokine-specific PCR products with digoxigenin (Dig) in a repeated PCR. This resulted in an intrinsic labelling of the probe with several Dig-UTP molecules. Incorporation of Dig-11-dUTPs was shown on ethidium bromide-stained agarose gels by a higher molecular weight of the PCR products with incorporated Dig-dUTPs when compared to control PCR products without digoxigenin. Cytospin-centrifuged cells of PHA-stimulated PBMC or lymphoid cell lines and frozen sections of various human lymphoid tissues were hybridized with the Dig-labelled cytokine probes and the hybridized probes were detected immuno-histochemically. In this way, we detected and localized cytokine mRNAs (IL-2, IL-4, IL-6, IL-8, IL-10) in PBMC, in the human T-cell line Jurkat, in the follicular lymphoma cell line DoHH2, and in human lymph nodes and tonsils. The in situ hybridization had a high sensitivity as the results correlated closely with the detection of cytokine mRNA by reverse transcriptase-PCR (RT-PCR) data from the same samples. We showed that Jurkat and DoHH2 cells produce several cytokines constitutively and that, after activation with the phorbol ester PMA, expression of several cytokine mRNAS was enhanced.
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PMID:An improved, sensitive, non-radioactive in situ hybridization method for the detection of cytokine mRNAs. 765 59

CD14 has been reported to function as a receptor for bacterial LPS complexed with serum proteins, transducing an activation signal for TNF-alpha production. We found that the anti-CD14 mAb MEM-18 inhibited not only LPS-induced release of TNF-alpha, but also LPS-induced, TNF-alpha independent release of IL-6 and IL-8 by human monocytes and alveolar macrophages. Inhibitory effect of MEM-18 was detected both in the presence of human or bovine calf serum and under serum-free conditions. In contrast, MEM-18 did not block release of these cytokines induced by IL-1 beta, TNF-alpha, PMA, and zymosan. We conclude that CD14 is involved in LPS-induced release of TNF-alpha, IL-6, and IL-8 by monocytes and alveolar macrophages and that this receptor appears to be able to recognize LPS directly in the absence of serum.
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PMID:Involvement of CD14 in lipopolysaccharide-induced tumor necrosis factor-alpha, IL-6 and IL-8 release by human monocytes and alveolar macrophages. 768 Oct 82

Cytokine responses are dramatically affected when HIV-1 infected cells are activated with certain antigenic stimuli. We report the effects of HIV-1 tat gene in cytokine modulation, using HIV-1 tat transfected T (Jurkat) and B (Raji) cell lines. Studying the effect of tat and/or PMA + PHA on mRNA expression of 14 cytokines (IL-1 alpha, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-alpha, TNF-beta, GM-CSF, TGF-beta, IFN-gamma and MIP-1 alpha) illustrated differential effects. In addition to the varied effects of tat on the steady state levels of cytokine mRNAs, tat induced the secretion of TNF-beta preferentially in both B and T cell lines, either by itself as in Raji B cell line or synergistically upon PMA + PHA stimulation as in Jurkat T cell line.
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PMID:Differential expression of cytokine genes in HIV-1 tat transfected T and B cell lines. 769 26


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