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)

The regulation of monocyte-derived neutrophil chemotactic factor (MDNCF)/interleukin 8 (IL 8) receptor expression by the MDNCF/IL 8 ligand was examined using freshly isolated human peripheral blood neutrophils. MDNCF/IL 8 down-regulated greater than 90% of its own receptor expression within 10 min at 37 degrees C. This down-regulation was associated with internalization of the ligand. The radiolabeled MDNCF/IL 8 molecules after internalization were proteolytically degraded, and trichloroacetic acid-soluble molecules were released into the culture medium starting at 60 min. Lysosomotropic agents could inhibit this degradation of ligand suggesting the involvement of lysosomal enzymes in this proteolytic digestion. MDNCF/IL 8 receptors reappeared on the cell surface within 10 min after removal of free ligands from the culture medium. Cycloheximide did not alter the reappearance of the receptor suggesting that de novo protein synthesis of MDNCF/Il 8 receptors is not involved in this event and that receptors probably recycled. The addition of lysosomotropic agents partially inhibited the reappearance/recycling of the receptors, although none of these agents inhibited the binding of ligand to the surface receptors or ligand internalization. Ammonium chloride reduced the MDNCF/IL 8-induced neutrophil chemotactic response in a dose-dependent fashion. These data suggest that MDNCF/IL 8 receptor expression is dynamically regulated by MDNCF/IL 8 and that the rapid recycling of MDNCF/IL 8 receptors may be essential for the chemotactic response of neutrophils.
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PMID:Interleukin 8 (monocyte-derived neutrophil chemotactic factor) dynamically regulates its own receptor expression on human neutrophils. 240 54

Induction of IL-8 gene expression was investigated in IL-2-stimulated circulating peripheral blood polymorphonuclear neutrophils (PMN). Brief exposure of normal PMN to human rIL-2 enhanced both transcriptional and translational expression of IL-8. The IL-8 mRNA was first detectable by 3 h, followed by a continuous maintenance of high mRNA levels up to 18 h. Maximal transcription was obtained with 1000 U/ml of IL-2, which achieved the level observed with known neutrophil-activating factors such as granulocyte macrophage-CSF and Candida albicans. The protein synthesis inhibitor, cycloheximide, had no detectable effect on levels of IL-8 mRNA expression in PMN incubated in medium alone; however, cycloheximide could selectively modulate IL-8 mRNA transcription in PMN, depending on the cytokine used. Cycloheximide did not affect or alter IL-8 mRNA induction in IL-2-treated PMN but abrogated it in granulocyte macrophage-CSF-treated PMN and super-induced the level of IL-8 mRNA in C. albicans-treated PMN. Of significance was the observation that IL-2 has no direct chemotactic effect on PMN, whereas the cell-free supernatants from IL-2-stimulated PMN show potent chemotaxis for freshly isolated PMN, which can be specifically blocked by anti-IL-8 Abs. These findings suggested that the induction of IL-8 gene expression in PMN by IL-2 may be involved in the recruitment of PMN into tissues during local IL-2 therapy in human cancer and in part contribute to tumor rejection.
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PMID:Induction of IL-8 gene expression in human polymorphonuclear neutrophils by recombinant IL-2. 814 38

Interleukin (IL)-8 is a member of the supergene family of proinflammatory and chemotactic cytokines recently termed chemokines. IL-8 has been implicated in the pathogenesis of inflammatory skin diseases such as psoriasis. In this study, IL-8 mRNA expression and protein production were determined in normal cultured human epidermal keratinocytes after ultraviolet-B (UVB) irradiation. Messenger RNA levels were determined by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Total RNA was extracted from cultured keratinocytes at various time points post-irradiation, reverse transcribed to cDNA, and amplified by PCR using a labeled specific primer for the target gene. Amplified products were sized by electrophoresis, visualized by autoradiography, and quantitated by densitometry. Autoradiographs were normalized relative to glyceraldehyde-3-phosphate-dehydrogenase (G3PDH) signals. Constitutive expression of IL-8 mRNA was seen in normal cultured keratinocytes. After 100 or 300 J/m2 UVB irradiation, a rapid increase in IL-8 mRNA level was observed within 1 h after irradiation. At 24 h after irradiation, the mRNA level was elevated 11-13 times compared with the control level. Production of IL-8 protein in culture supernatants was assayed by enzyme-linked immunosorbent assay (ELISA). Significant levels of IL-8 protein were observed at 24 h after irradiation. Cycloheximide treatment blocked this IL-8 protein induction. As IL-8 is known to be an inflammatory cell chemotactic factor, these results suggest a possible role for IL-8 in UVB-induced skin inflammation and diseases.
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PMID:IL-8 gene expression and production in human keratinocytes and their modulation by UVB. 822 30

In addition to T cells, NK cells, B cells, and monocytes, we provide new evidence that human polymorphonuclear neutrophils (PMN) can be functionally activated by IL-2 via binding to IL-2R beta expressed on the cell surface. Brief exposure of normal PMN to human rIL-2 enhanced both transcriptional and translational expression of TNF-alpha. The release of TNF-alpha protein by IL-2-treated PMN was inhibitable by a specific mAb against human IL-2-R beta. The response to IL-2 was dose and time dependent with the increase in TNF-alpha mRNA detected maximally 3 h after IL-2 exposure, followed by a continuous maintenance of high mRNA levels up to 18 h. The TNF-alpha mRNA was significantly increased above the medium control level, with as little as 10 U/ml of IL-2. Maximal transcription was obtained with 1000 U/ml of IL-2, which achieved the level observed with known neutrophil activating factors such as granulocyte-macrophage-CSF, IL-8, and Candida albicans. Using actinomycin D, it was found that new and continuous synthesis of a labile TNF-alpha mRNA was responsible for the observed high levels of transcripts. Of significance was the observation that cycloheximide could selectively modulate TNF-alpha mRNA transcription in neutrophils, depending on the cytokine used. Cycloheximide did not affect or alter TNF-alpha mRNA induction in IL-2-treated neutrophils but abrogated it in granulocyte-macrophage-CSF-treated neutrophils and superinduced transcription in C. albicans-treated neutrophils. Thus various control elements must be involved in the transcription of the TNF-alpha genes that are responsive to different cytokines and activating factors. The induction of TNF-alpha and functional activation of neutrophils by IL-2 is therefore an important immunomodulatory property of IL-2 that has not heretofore been recognized.
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PMID:Activation of tumor necrosis factor-alpha production from human neutrophils by IL-2 via IL-2-R beta. 843 29

Interleukin(IL-)6 is overproduced in psoriatic lesions. We investigated the contribution of dermal fibroblasts to the local IL-6 production. Fibroblasts (passageno. 2 to 6) derived from lesional psoriatic (PP) and normal human (NN) skin were used to analyse the secretion of IL-6, and the related cytokines IL-1, IL-8 and TNF-alpha, and the expression of their corresponding mRNA by bioassay, ELISA and Northern hybridization, respectively. PP fibroblasts cultured under serum-free conditions produced increased amounts of bioactive IL-6 when compared to NN fibroblasts. Differences were partially restored in the presence of growth factors or serum. The serum-induced IL-6 production reached a maximum within 24 h after seeding and remained unchanged in PP fibroblasts, whereas comparable amounts of IL-6 were produced only 6 days later in NN fibroblasts. There was a clear expression of IL-6 mRNA in both types of fibroblasts under serum-free conditions. Unexpectedly, fetal calf serum, inactivated fetal calf serum as well as human serum completely inhibited the expression of IL-6 mRNA in all the PP fibroblast cultures investigated. NN fibroblasts were clearly less sensitive to this inhibiting effect of serum. Furthermore, medium supplemented with serum-free component or calcium also repressed IL-6 mRNA expression in PP fibroblasts in contrast to NN fibroblasts. Cycloheximide fully restored the repressing effect of serum indicating that serum induced a labile repressor protein. PP and NN fibroblasts produced negligible amounts of IL-1 and TNF-alpha, but the production of IL-8, however, was comparable to that of IL-6. Our results show a differently regulated IL-6 synthesis in PP fibroblasts in vitro, suggesting an active contribution of dermal fibroblasts to the local IL-6 production in psoriasis.
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PMID:Expression of cytokines and their receptors by psoriatic fibroblast. I. Altered IL-6 synthesis. 874 69

Inhibition of protein synthesis may result in superinduction of short-lived transcripts and has been attributed variably to stabilization of transcripts and/or increased gene transcription. Little is known about the kinetics of these processes and relevant transcriptional elements have not been identified. In this study, we describe superinduction of interleukin 8 (IL-8) mRNA, an important inflammatory mediator, in lung epithelial-like H292 cells and identify the underlying molecular mechanisms and their kinetics. Cycloheximide (CHI, 10 microg/ml), an inhibitor of protein synthesis, maximally increased IL-8 mRNA levels 30-fold in H292 cells. Tumour necrosis factor alpha (TNF-alpha), which induced IL-8 mRNA 3-fold, synergized with CHI causing a 150-fold increase at 6 h. CHI early on increased the stability of IL-8 mRNA (from 40 min in cells cultured with medium to more than 4 h with CHI). CHI also increased transcription as shown by transfection with IL-8 promoter constructs. Truncated and mutated constructs identified NF-kappaB and AP-1 binding sites as primary cis-acting elements in IL-8 gene transcription and IL-8 mRNA superinduction. Electrophoretic mobility shift assays indicated that CHI increased NF-kappaB and prolonged AP-1 DNA-binding activities and that the synergism of TNF-alpha and CHI on IL-8 mRNA expression was paralleled by a further increase of AP-1 DNA-binding activity. This synergism was still noticed when 4 h elapsed between the addition of CHI and that of TNF-alpha. Taken together, our results indicate that CHI interferes with both post-transcriptional and transcriptional repressive mechanisms of IL-8 mRNA expression.
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PMID:Enhanced AP-1 and NF-kappaB activities and stability of interleukin 8 (IL-8) transcripts are implicated in IL-8 mRNA superinduction in lung epithelial H292 cells. 946 40

Secretory group II (sPLA2) and cytosolic (cPLA2) phospholipases A2 and cyclooxygenase-2 (Cox-2) play a pivotal role in release of proinflammatory eicosanoids. Excessive activity of sPLA2 per se can also propagate inflammation. Endogenous control of the above enzymes has not been completely elucidated. We investigated the combined impact of promoting cytokines and inhibitory peptide growth factors on the expression of mRNA of the above enzymes, on protein content and extracellular release of sPLA2 and on PGE2 production in osteoblasts (FRCO). The synthesis and release of sPLA2 were enhanced by about 20-fold by 0.5 ng/ml IL-1beta or by 50 ng/ml of TNFalpha. Coaddition of both cytokines resulted in synergistic 150-fold increase in the release of sPLA2 implying the existence of two paths of induction. IL-1beta and TNFalpha markedly enhanced the transcription of sPLA2 mRNA. Kinetic study showed that IL-1/TNF initiated sPLA2 release after 12 h, reaching maximum at 48 h. IL-1alpha was a weak stimulator of sPLA2 release, whereas IL-6, IL-8, IGF, IFN-gamma, growth hormone, insulin and GM-CSF were not stimulatory. Peptide growth hormones TGFbeta, PDGF-BB, EGF and bFGF markedly inhibited the extracellular release of sPLA2. TGFbeta and PDGF-BB significantly reduced the level of sPLA2 mRNA, thus acting upon transcription whereas EGF and bFGF were not inhibitory, acting rather upon the translational or posttranslational steps. IL-1/TNF and growth factors had no significant effect on cPLA2 mRNA expression. Cox-2 mRNA expression was markedly enhanced by IL-1/TNF and suppressed by all growth factors tested. Cytokines enhanced the extracellular release of PGE2 and further enhancement was induced by growth factors with the exception of TGFbeta. Cycloheximide abolished completely the release of sPLA2 and markedly reduced the release of PGE2 from cytokine-stimulated FRCO, regardless of whether growth factors were present or not. NS-398, a specific inhibitor of Cox-2 abolished almost completely the release of PGE2 from cytokine-stimulated cells, regardless of the presence of growth factors. Thus, different signalling mechanisms are involved in the impact of growth factors on mRNA expression of sPLA2, cPLA2 and Cox-2. The differences between the impact on FRCO sPLA2 and that reported in other cells, imply that endogenous control of arachidonic acid cascade is cell-specific.
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PMID:Regulation of the cellular expression of secretory and cytosolic phospholipases A2, and cyclooxygenase-2 by peptide growth factors. 962 92

IL-8, a potent neutrophil chemoattractant that is elevated about 200-fold in exudative neutrophils isolated from localized inflammatory sites in vivo, is thought to play a major role in recruitment of neutrophils to inflammatory sites. Incubation of peripheral blood neutrophils with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-sequestering-ATPase, causes a dose-dependent induction of IL-8 synthesis that continues for up to 8 h. Cycloheximide inhibits the thapsigargin-induced IL-8 production, suggesting the induction of protein synthesis de novo. In addition, Northern blot analysis of mRNA isolated from neutrophils indicates that thapsigargin treatment increases IL-8 mRNA in a time- and dose-dependent manner. Thapsigargin also induces a biphasic rise in the intracellular Ca2+ concentration, [Ca2+]i, which is composed of an initial (within 15 s) EGTA-insensitive elevation in [Ca2+]i, followed by a delayed (2-min) EGTA-sensitive component. Addition of EGTA before thapsigargin inhibited the induction of IL-8 production. Experiments in which EGTA was added at various times after thapsigargin treatment indicated that a sustained Ca2+ influx was required for maximum IL-8 production. Ascomycin and cyclosporin A, inhibitors of the Ca2+-dependent phosphatase, calcineurin, also inhibited thapsigargin-induced IL-8 production. Thus, in neutrophils, a prolonged increase in [Ca2+]i stimulates IL-8 transcription and synthesis, possibly through a calcineurin-dependent pathway.
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PMID:Ca2+-dependent production and release of IL-8 in human neutrophils. 978 Feb 10

Exposure to fluorides has been associated with asthmatic symptoms among workers in the aluminium industry. In a recent experimental study hydrogen fluoride (HF) was found to induce a weak inflammatory response in humans. In the present study the potential of sodium fluoride (NaF) and HF to induce cytokine response was examined and how these responses are modulated by Al3+ in a human epithelial lung cell line (A549). Dose-response experiments showed a maximal release of IL-6 and IL-8 at a concentration of 5 mM NaF 24 h after addition. The responses to HF were of a similar magnitude as for NaF. Time-course experiments showed a NaF-induced IL-6 response at 5 h, whereas an IL-8 response was observed after 10 h. Cycloheximide treatment completely abolished the NaF-induced cytokine responses. A marked increase in the mRNA level for IL-6 was observed already 2 h after exposure to 5 mM NaF, and presumably is a prerequisite for the subsequent increase of IL-6. The fluoride-induced effects on IL-6 and IL-8 release were strongly reduced by pretreatment with deferoxamine (an Al3+-chelator), and enhanced by addition of Al3+. This indicates that an AlF4-- complex, a known activator of GTP-binding proteins, is involved in fluoride-induced IL-6 and IL-8 responses in A549 cells.
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PMID:Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial lung cells. 1060 88

IL-10 has a wide range of effects tending to control inflammatory responses. We used flow cytometry to study IL-10 binding at the polymorphonuclear neutrophil (PMN) surface and its modulation by various proinflammatory agents. Little IL-10 bound to the surface of resting PMN. However, binding was strongly increased after stimulation with LPS and proinflammatory cytokines such as TNF and GM-CSF. IL-1 and IL-8 did not significantly modify IL-10 binding. Cycloheximide had no effect on TNF-induced IL-10 binding, strongly suggesting the release of a pre-existing pool of IL-10R rather than de novo receptor synthesis by PMN. This was confirmed by the inhibitory effect of pentoxifylline, an inhibitor of degranulation. The existence of an intracellular pool of IL-10R was shown by flow cytometry, immunocytochemical staining, and Western blotting with several anti-human IL-10R Abs. In subcellular fractions of resting PMN, IL-10R was mainly located in the specific granule fraction, and was absent from azurophil granules and cytosol. We also tested the mobilization of specific granules by measuring the release of lactoferrin, their reference marker. The differential effects of the proinflammatory agents on IL-10 binding matched their effects on lactoferrin release and may therefore be related to differential mobilization of specific granules by these agents. Furthermore, the kinetics of TNF-induced up-regulation of IL-10 binding to PMN ran parallel to the kinetics of the inhibitory effect of IL-10 on the oxidative burst, suggesting a key role of IL-10R mobilization from specific granules to the membranes in optimal regulation of inflammatory responses.
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PMID:Intracellular pool of IL-10 receptors in specific granules of human neutrophils: differential mobilization by proinflammatory mediators. 1129 Aug 4

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