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)

Gro beta and IL-8 are two pro-inflammatory cytokines with chemotactic activities on neutrophils. Binding studies were performed to ascertain whether their similar biological activities are mediated through the same receptor. Since Gro beta lacks tyrosine residues, recombinant Gro beta containing an additional carboxyterminal tyrosine residue (Gro beta-Tyr) was produced in transfected COS cells, purified to homogeneity and radiolabelled with 125INa. Saturation experiments using [125I]-Gro beta-Tyr allowed us to identify high affinity receptors on human neutrophils (Kd: 2 +/- 0.5 nM and Bmax: 4760 +/- 761 sites/cell). Experiments using [125I]-IL-8 as ligand, showed no significative differences in affinity (Kd: 4 +/- 0.9 nM) but about two times the number of sites (11316 +/- 1810 sites/cell). In competition experiments using [125I]-Gro beta-Tyr, unlabelled IL-8 and Gro beta-Tyr generated superposable displacement curves (IC50: 0.69 +/- 0.15 nM and 0.42 +/- 0.11 nM, respectively). Interesting, IL-8 binding sites could be down-regulated by Gro beta and IL-8, indicating that the two binding sites may be associated. Cross-linking experiments using [125I]-IL-8 revealed two major bands at 70 and 140 kDa, whereas experiments with [125I]-Gro beta-Tyr showed only the 70 kDa band. Taken together, these results suggest that the human neutrophil IL-8/Gro beta receptor is a dimeric complex with two high affinity binding sites for IL-8 and of those two, only one is shared by Gro beta.
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PMID:Functional linkage of the Gro beta and IL-8 receptors on the surface of human neutrophils. 821 44

Interleukin-8 (IL-8) is one of the major mediators of the inflammatory response. The pathways by which IL-8 activates inositide-specific phospholipase C (PLC) were investigated by co-expression of different components of the guanosine triphosphate binding protein (G protein) pathway in COS-7 cells. Two distinct IL-8 receptors reconstituted ligand-dependent activation of endogenous PLC when transfected together with the G protein alpha subunits G alpha 14, G alpha 15, or G alpha 16. However, reconstitution was not observed with cells that overexpressed G alpha q or G alpha 11. Furthermore, IL-8 receptors interacted with endogenous pertussis toxin-sensitive G proteins or with the recombinant G protein Gi to release free beta gamma subunits that could then specifically activate the beta 2 isoform of PLC. These findings suggest that IL-8 acts through signal-transducing pathways that are limited to specific heterotrimeric G proteins and effectors. These may provide suitable targets for the development of anti-inflammatory agents.
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PMID:G protein-coupled signal transduction pathways for interleukin-8. 831 40

Interleukin-8 (IL-8), neutrophil activating peptide-2 (NAP-2), and growth regulated gene (GRO, also known as melanoma growth stimulatory activity) are members of a family of peptides which are chemotactic agents for inflammatory cells such as neutrophils. Receptors have been identified for IL-8, GRO and NAP-2 on human neutrophils and granulocytic cell lines, and it has been observed that these cytokines can cross-compete for binding to a common receptor. Using the recently characterized rabbit IL-8 receptor as a probe, two classes of cDNAs, termed type 1 and type 2, were isolated from a human neutrophil library. The type 1 receptor binds only IL-8 while the type 2 receptor binds IL-8, GRO and NAP-2 at high affinity when respective cDNAs are expressed in COS-7 cells. The two cDNAs encode proteins that have an amino acid sequence identity of 77% while the type 1 and 2 receptors have an identity of 84 and 74% with the rabbit IL-8 receptor. These receptors also show significant homology with receptors for other chemotactic agents and with potential coding regions from the human cytomegalovirus genome.
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PMID:Molecular characterization of receptors for human interleukin-8, GRO/melanoma growth-stimulatory activity and neutrophil activating peptide-2. 838 12

A novel member of the interleukin-1 receptor family has been cloned by polymerase chain reaction using degenerate oligonucleotide primers derived from regions of sequence conservation, using as template a yeast artificial chromosome known to contain both interleukin-1 (IL-1) receptors and T1/ST2. The new receptor, called IL-1 receptor-related protein or IL-1Rrp, fails to bind any of the known IL-1 ligands. A chimeric receptor, in which the IL-1Rrp cytoplasmic domain is fused to the extracellular and transmembrane regions of the IL-1 receptor, responds to IL-1 following transfection into COS cells by activation of NFkappaB and induction of IL-8 promoter function.
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PMID:IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP. 862 25

IL-18 and IL-12 are major IFN-gamma-inducing cytokines but the unique synergism of IL-18 and IL-12 remains unclear. In the human NK cell line NKO, IL-18R alpha, and IL-18R beta are expressed constitutively but IL-18 did not induce IFN-gamma unless IL-12 was present. COS-1 fibroblasts, which produce the chemokine IL-8 when stimulated by IL-1 beta or TNF-alpha, do not respond to IL-18, despite abundant expression of the IL-18R alpha chain. COS-1 cells lack expression of the IL-18R beta chain. The IL-18R beta cDNA was cloned from a human T-B lymphoblast cDNA library and COS-1 cells were transiently transfected with the IL-18R beta chain and a luciferase reporter. In transfected COS-1 cells, IL-18 induced IL-8 and luciferase in the absence of IL-12 and independently of IL-1 and TNF. Ab against the IL-18R alpha chain, however, prevented IL-18 responsiveness in COS-1 cells transfected with the IL-18R beta chain, suggesting that both chains be functional. In NKO cells and PBMC, IL-12 increased steady-state mRNA levels of IL-18R alpha and IL-18R beta; the production of IFN-gamma corresponded to IL-12-induced IL-18R alpha and IL-18R beta chains. We conclude that functional reconstitution of the IL-18R beta chain is essential for IL-12-independent proinflammatory activity of IL-18-induced IL-8 in fibroblasts. The synergism of IL-18 plus IL-12 for IFN-gamma production is, in part, due to IL-12 up-regulation of both IL-18R alpha and IL-18R beta chains, although postreceptor events likely contribute to IFN-gamma production.
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PMID:Functional reconstitution and regulation of IL-18 activity by the IL-18R beta chain. 1112 87

The transforming growth factor-beta1 (TGF-beta1) responsive epithelial non-small-cell lung cancer (NSCLC) cell line NCI-H727 was used to identify potential target genes involved in TGF-beta1-mediated responses. Comparative cDNA expression patterns between cells treated with TGF-beta1 and those treated with vehicle were generated by differential mRNA display. One 496-bp fragment, differentially increased threefold by TGF-beta1 and hybridizing to a 2.7-kb mRNA species in NCI-H727 cells by Northern analysis, revealed no significant match to any known gene sequence. The mRNA transcript of this novel gene that we named differentially expressed nucleolar TGF-beta1 target (DENTT) is expressed in several normal human tissues, with the highest level of expression in brain. Human brain cDNA library screening and 5' rapid amplification of cDNA ends yielded full-length DENTT cDNA containing an 1899-bp open reading frame encoding a predicted 633-amino-acid protein with four potential nuclear localization signals (NLSs) and two coiled-coil regions. DENTT contains a conserved 191-residue domain that shows significant identity to, and defines, the TSPY/TSPY-like/SET/NAP-1 superfamily. Enhanced green fluorescent protein (EGFP)-tagged full-length DENTT transfected into COS-7 cells showed nucleolar and cytoplasmic localization. Transfection of EGFP-tagged DENTT NLS deletion constructs lacking the bipartite NLS-1 were excluded from the nucleolus. While NLS-1 is necessary for nucleolar localization of DENTT, it is not sufficient for sole nucleolar localization. Our data show that DENTT mRNA induction by TGF-beta1 correlates with induction of TGF-beta1 mRNA, induction of extracellular matrix gene expression, and inhibition of colony formation in soft agarose in TGF-beta1 responsive NSCLC cells when exposed to TGF-beta1. TGF-beta1 does not induce DENTT mRNA expression in TGF-beta1 nonresponsive NSCLC cells. Our data suggest that this novel TGF-beta1 target gene has distinct domains for direction to different subnuclear locations.
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PMID:Identification of differentially expressed nucleolar TGF-beta1 target (DENTT) in human lung cancer cells that is a new member of the TSPY/SET/NAP-1 superfamily. 1131 8

A novel gene, designated ML-1, was identified from a human genomic DNA clone and human T cell cDNA sequences. The second exon of ML-1 gene shares significant sequence identity with the gene encoding IL-17 (IL-17). ML-1 gene expression was up-regulated in activated PBMCs, CD4(+) T cells, allergen-specific Th0, Th1, and Th2 clones, activated basophils, and mast cells. Increased expression of the ML-1 gene, but not IL-17, was seen following allergen challenge in four asthmatic subjects, suggesting its role in allergic inflammatory responses. ML-1 from transiently transfected COS-7 cells was able to induce gene expression and protein production for IL-6 and IL-8 (at 10 ng/ml of ML-1: for IL-6, 599.6 +/- 19.1 pg/ml; for IL-8, 1724.2 +/- 132.9 pg/ml; and at 100 ng/ml of ML-1: for IL-6, 1005.3 +/- 55.6 pg/ml; for IL-8, 4371.4 +/- 280.5 pg/ml; p < 0.05 for both doses vs baseline) in primary bronchial epithelial (PBE) cells. Furthermore, increased expression of ICAM-1 was found in ML-1-stimulated PBE cells (mean fluorescence intensity (MFI) = 31.42 +/- 4.39 vs baseline, MFI = 12.26 +/- 1.77, p < 0.05), a functional feature distinct from IL-17 (MFI = 11.07 +/- 1.22). This effect was not inhibited by a saturating amount of IL-17. These findings demonstrate that ML-1 is a novel cytokine with a distinct function, and suggest a different receptor for ML-1 on PBE cells.
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PMID:Identification of a novel cytokine, ML-1, and its expression in subjects with asthma. 1159 68

Differentially expressed nucleolar TGF-beta1 target (DENTT) is a recently identified gene whose mRNA is differentially affected by TGF-beta1 in TGF-beta1-responsive human lung cancer cells and who is a new member of the TSPY/TSPY-like/SET/NAP-1 (TTSN) protein superfamily. Here, we report that mouse DENTT mRNA contains a 2031-bp open reading frame that encodes a predicted polypeptide of 677-amino acids with a relative molecular mass of 77,671 Da. The mouse and human DENTT sequences show 77% and 78% homology at the nucleotide and amino acid level, respectively. Mouse DENTT is predicted to be a nuclear protein with two nuclear localization signals (NLS), two coiled-coil regions, and a domain that shows significant identity to a region that defines the TTSN superfamily. Green fluorescent protein (GFP)-tagged full-length mouse DENTT transfected into COS-7 cells showed localization predominantly in the nucleolus. Reverse transcription-polymerase chain reaction amplification, Northern hybridization, and Western blot analyses showed expression of mouse DENTT mRNA and protein throughout mouse embryogenesis. Immunohistochemical staining analysis showed that DENTT is expressed in multiple tissues in a defined spatiotemporal pattern during mouse embryogenesis. The heart and primitive brain were the first organs of the embryo that showed immunoreactivity for the DENTT antibody by day 8 of development (E8). In the developing mouse brain, the choroid plexus was intensely stained for DENTT in all stages of development. The spinal cord and dorsal root ganglia were also positive for DENTT staining beginning in the 11-day-old embryo (E11), where homogeneous immunostaining was observed throughout the developing neurons. By day 16 of development (E16), only a small subset of the neuronal population in the spinal cord and dorsal root ganglia was positively stained for DENTT. DENTT immunoreactivity increased steadily with maturation as the differentiation of cartilage and osteoblasts proceeded and reached a maximum in the growth plate during endochondral ossification. DENTT expression was also detected in multiple rodent cell types in vitro, including mouse F9 embryonal carcinoma (EC) cells. Addition of retinoic acid or sodium butyrate to F9 EC cells showed a rapid decrease in expression of DENTT protein occurring by 1 hr that continued to decrease to almost undetectable levels after 24 hr. Cotransfection of full-length mouse DENTT expression plasmid with 3TPLux or COL7A1Luc Luciferase reporter plasmids into F9 EC cells significantly increased the level of 3TPLux reporter transcription while decreasing the level of COL7A1Luc reporter transcription, suggesting that DENTT may play multiple roles in modulating transcriptional responses. These findings suggest new roles for the TTSN superfamily during embryogenesis and differentiation.
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PMID:Differentially expressed nucleolar TGF-beta1 target (DENTT) in mouse development. 1261 35

Heterophils, the principal avian polymorphonuclear leukocytes (PMNs) equivalent to the mammalian neutrophil, function as professional phagocytes against bacterial infections, mediate acute inflammation, and respond to cytokine stimulation to aid in regulation of innate host defenses. Interleukin-2 (IL-2) has been found to exercise an array of biological effects on other cell types besides T lymphocytes, including NK cells, B cells, monocytes, and neutrophils. In the present experiments, using real-time quantitative RT-PCR, we evaluated the role of rChIL-2 as a priming mediator controlling heterophil responses at the level of gene transcription by examining the expression of mRNA for pro-inflammatory (IL-1beta, IL-6, IL-8) and Th1 (IL-18 and IFN-gamma) cytokine genes following stimulation with phagocytosis agonists; i.e., opsonized and nonopsonized Salmonella enteritidis. Peripheral blood heterophils were isolated and incubated with rChIL-2 from transfected COS cells. rChIL-2 selectively primed the heterophils for an increase in transcription of the pro-inflammatory cytokine IL-8 and of the Th1 cytokine IL-18 induced by all three phagocytic agonists. Although rChIL-2 priming modulated the expression of specific cytokine mRNA in heterophils stimulated by different phagocytic agonists, the rChIL-2 by itself did not directly induce gene expression of either the pro-inflammatory or Th1 cytokines. We propose that rChIL-2 could be priming heterophils solely to function as more efficient innate effector cells to limit bacterial growth through the selective increase of IL-8 and IL-18 gene expression.
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PMID:Priming by recombinant chicken interleukin-2 induces selective expression of IL-8 and IL-18 mRNA in chicken heterophils during receptor-mediated phagocytosis of opsonized and nonopsonized Salmonella enterica serovar enteritidis. 1459 63

Although medroxyprogesterone acetate (MPA) is used as an injectable contraceptive, in hormone replacement therapy (HRT) and in treatment of certain cancers, the steroid receptors and their target genes involved in the actions of MPA are not well understood. We show that MPA, like dexamethasone (dex), significantly represses tumour necrosis factor (TNF)-stimulated interleukin-6 (IL-6) protein production in mouse fibroblast (L929sA) cells. In addition, MPA repressed IL-6 and IL-8 promoter-reporter constructs at the transcriptional level, via interference with nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1). Furthermore, like dex, MPA does not affect NFkappaB DNA-binding activity. We also observed significant transactivation by MPA of a glucocorticoid response element (GRE)-driven promoter-reporter construct in both L929sA and COS-1 cells. The MPA-induced nuclear translocation of the glucocorticoid receptor (GR), as well as the antagonistic effects of RU486, strongly suggest that the actions of MPA in these cells are mediated at least in part via the GR.
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PMID:Medroxyprogesterone acetate downregulates cytokine gene expression in mouse fibroblast cells. 1522 34


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