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)

Phorbol ester (TPA) and retinoic acid (RA) are two potent immunomodulatory agents whose actions are mediated through distinct signal transduction pathways involving protein kinase C (PKC) and nuclear RA receptors, respectively. We have investigated the interactions between these two pathways in the regulation of expression of the inflammatory cytokine IL-8 in human skin fibroblasts. TPA (as previously reported) and RA both induced IL-8 mRNA and protein in a time- and dose-dependent manner. IL-8 mRNA induction by TPA (10 nM) was maximal (15-fold) within 6 h, and returned to baseline within 24 h of treatment, although maximal induction (10-fold) by RA (1 microM) did not occur until 24 h posttreatment. Induction of IL-8 by TPA was blocked by 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine, which inhibits PKC and cAMP-dependent protein kinases (PKA), but not by N-(2-ganidinoethyl)-5-isoquinoline sulfonamide, which preferentially inhibits PKA, consistent with the participation of PKC in the induction of IL-8 by TPA. In contrast, induction of IL-8 by RA was inhibited by both 1-(5-isoquinoline sulfonamide and N-(2-gamidinoethyl)-5-isoquinoline sulfonamide, suggesting the participation of PKA in the induction of IL-8 by RA. However, activation of PKA by addition of cAMP analogues was not sufficient to induce IL-8 expression. Induction of IL-8 by RA also did not appear to be mediated indirectly through induction of IL-1, because addition of IL-1R antagonist did not block IL-8 induction by RA. RA and TPA added in combination synergistically enhanced expression of IL-8 mRNA, measured at 6 (2-fold) and 24 h (10-fold) posttreatment. To investigate the mechanism of this synergy, the effect of TPA and RA on fibroblast PKC activation and PKC isozyme levels were determined. TPA, either alone or together with RA, but not RA alone, stimulated phosphorylation of an endogenous 80-kDa PKC substrate. Dermal fibroblasts expressed three PKC isozymes (alpha, (delta, and (epsilon). TPA, but not RA, down-regulated PKC-alpha, neither TPA or RA affected the level of PKC-delta, and both TPA and RA down-regulated PKC-epsilon. This latter effect was enhanced 2-fold by addition of RA and TPA together. These data suggest that modulation of PKC-epsilon may be a common participant in the regulation of IL-8 expression by TPA and RA.
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PMID:Retinoic acid and phorbol ester synergistically up-regulate IL-8 expression and specifically modulate protein kinase C-epsilon in human skin fibroblasts. 132 13

Four tumor promoters, i.e. PB, TPA, NAF, and DDT, added singly to a calcium-deprived synthetic medium, elicited early and late mitogenic effects and concurrent surges of nuclear poly(ADP-ribose) polymerase (pADPRP) activity in primary neonatal rat hepatocytes mutagenized with an intra-uterine dose of DMN. These actions were fully abated by the pADPRP inhibitor 3-MBA. Conversely, EGF only acted as a full mitogen when medium's calcium was at physiological levels, and its effects could not be blocked by 3-MBA. The same tumor promoters, but not EGF, also evoked a swift and lingering amplification of pADPRP transcripts in DMN-initiated hepatocytes kept in low-calcium medium. Hence, a coordinated modulation of both pADPRP transcripts and activity by xenobiotics is likely to be involved in the clonal expansion of early preneoplastic hepatocytes.
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PMID:The exposure of carcinogen-initiated primary neonatal rat hepatocytes to tumor promoters modulates both the transcripts and the enzymatic activity of nuclear poly(ADP-ribose) polymerase. 154 Jan 55

Interleukin-8 (IL-8/NAP-1), the neutrophil-activating peptide 2 (NAP-2), and formyl-peptides (fMLP) have been described as potent stimulators for human neutrophils (PMN). We have compared the mechanism of signal transduction induced by these factors during neutrophil activation (elastase release), by using activators and inhibitors and by direct measurement of the enzymatic activity of kinases. Moreover, costimulation kinetics of the combined factors were analyzed. Our results show that each of these stimulators induces elevated levels of cAMP, indicating the activation of adenylate-cyclase. Further results obtained with the kinase inhibitor H-7 and the cAMP analogue dibutyryl-cAMP (dbcAMP) gave evidence that cAMP-dependent kinases are involved in the down-regulation of the activation process. Degranulation could not be prevented by the inhibitor W-7, nor did the treatment of cells with calcium ionophore (A23187) lead to elevation of intracellular calcium levels. Both phenomena exclude the participation of calcium calmodulin-dependent kinases. Further results obtained with the novel protein kinase C (PKC) inhibitor BM 41440 as well as by direct measurement of PKC enzyme activity demonstrated the involvement of PKC in fMLP-mediated stimulation but not with IL-8/NAP-1 or NAP-2. Analysis of costimulation experiments conducted with these three factors and TPA confirmed these results and gave evidence that fMLP activates two different signaling pathways, one of which is PKC dependent, while the other is not. Moreover, our data indicate that NAP-2, IL-8/NAP-1, and fMLP use identical PKC-independent transduction mechanisms.
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PMID:Neutrophil-activating polypeptides IL-8 and NAP-2 induce identical signal transduction pathways in the regulation of lysosomal enzyme release. 165 69

The pleiotropic nature of malignant fibrous histiocytomas (MFH) is manifested as mixed cellular infiltrates consisting of myofibroblasts, histiomonocytes, and neutrophils. We detail in this report the phenotypic characteristics of the human fibrous histiocytoma giant cell tumor (GCT) cell line that establish its mesenchymal origin. The latter is underscored by the ability of GCT cells to express mRNA for transforming growth factor beta (TGF-beta) as well as both A and B chains of platelet-derived growth factor (PDGF). GCT cells also support the binding of CD34+ cells, but less efficiently than do normal marrow stromal cells. Since cytokines elaborated by MFH may mediate in part the recruitment of monocytes and neutrophils into tumor-infiltrated tissues, we have determined the cytokine repertoire of the GCT cell line, already known for its ability to elaborate colony-stimulating factors (CSFs) and interleukin-1 (IL-1). GCT cells express IL-1 alpha, IL-1 beta, IL-6, macrophage colony-stimulating factor (M-CSF or CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and IL-8. No detectable mRNA for IL-3, IL-4, IL-7, and tumor necrosis factor-alpha (TNF-alpha) was detected in GCT cells by polymerase chain reaction (PCR). Expression of cytokine mRNAs was responsive to agents such as dexamethasone (dex), 12-O-tetradecanoyl phorbol 13-acetate (phorbol diester or TPA), and TNF-alpha. Thus, this cell line provides a useful model for understanding the pathobiology of MFH and hematopoietic progenitor interactions with mesenchymal/stromal cells.
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PMID:Phenotypic characterization of the human fibrous histiocytoma giant cell tumor (GCT) cell line and its cytokine repertoire. 768 82

In human fibroblast cultures TPA increased IL-6 and IL-8 production. This was reduced by vitamin D3 metabolites and analogs. The two analogs employed: 1,25 (OH)2-22 (E)-dehydro-24-monohomo vitamin D3 (Compound A) and 1,25 (OH)2 -22 (E)-dehydro-24 dihomo-vitamin D3 (Compound B) may be useful in the therapy of pathologic proliferative disorders including psoriasis, particularly since they are less toxic and have less effect on calcium metabolism than vitamin D3.
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PMID:Inhibition of IL-6 and IL-8 production in human fibroblast cell lines by 1,25 (OH)2 vitamin D3 and two of its analogs with lower calcemic activity. 820 27

The objective of this study was to characterize interleukin-1, -6, and -8 (IL-1-, IL-6-, and IL-8)-induced prostacyclin (PGI2 as 6-keto PGF1 alpha) and prostaglandin E2 (PGE2) production in primary cultures of human myometrial cells. Prostaglandins (PGs) released into the culture media were quantitated by specific radioimmunoassays. IL-1, but not IL-6 or IL-8, caused a dose- and time-dependent increase in the production of both PGI2 and PGE2. Half-maximally stimulating doses (EC50) of IL-1 were about 0.1 ng/ml, and maximal responses were observed at 1-10 ng/ml, amounting to 15- to 23-fold increases over unstimulated controls. The action of IL-1 was greatly potentiated by the protein kinase C-activating phorbol ester, TPA, and inhibited by actinomycin D and cycloheximide. IL-1-induced PG production was also suppressed by dexamethasone, by the natural IL-1 receptor antagonist (IL-1ra), and by transforming growth factor1 beta (TGF1 beta). It is concluded that IL-1 is a potent agonist of PG synthesis in human myometrial cells, acting by a mechanism dependent on the synthesis of new proteins, presumably key enzymes (phospholipase A2 and/or cyclo-oxygenase-2). This study has added further support to the notion that the myometrium serves as a target for the inflammatory cytokine, IL-1, and thereby may be affected directly, thus promoting preterm labor associated with intrauterine infection.
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PMID:Effect of cytokines on prostaglandin E2 and prostacyclin production in primary cultures of human myometrial cells. 879 88

The urocanic acid cis isomer (cis-UCA) is a possible cutaneous photoreceptor for the immunomodulatory phenomena that follow ultraviolet B irradiation. Several experiments in animals show an inhibitory action of cis-UCA on cellular immunity. However, the action of cis-UCA on the synthesis of cytokines in keratinocytes remains unknown. Long-term cultures of normal human keratiocytes were prepared in a serum-free medium, and stimulated with 1 microgram/ml of phorbol 12-myristate 13-acetate (TPA) and UCA or UVB-UCA (10-100 micrograms/ml). Synthesis of the following cytokines was measured using ELISA and Northern blot techniques: TNF-alpha, IL-1 alpha, IL-1 beta, IL-6, IL-8 and TGF-beta 1. TPA increased TNF-alpha protein levels in culture supernatants. No changes in Il-1 alpha and IL-1 beta protein levels were detected in basal culture supernatant after TPA stimulus. TPA augmented RNA expression for TNF-alpha, IL-1 alpha, IL-1 beta and TGF-beta 1. UCA isomers did not induce cytokine changes in protein synthesis. Expression of IL-1 alpha and IL-1 beta genes was increased after exposure to 100 micrograms/ml UVB-UCA (70 micrograms/ml cis-UCA). A slight increase in TNF-alpha RNA expression was detected when the dose of UVB-UCA reached 100 micrograms/ml. No effects on cytokine synthesis were found after UCA stimulus. These results suggest that low doses of cis-UCA do not effect cytokine synthesis by keratinocytes.
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PMID:Effects of low concentrations of cis- and trans-urocanic acid on cytokine elaboration by keratinocytes. 918 8

Pentoxifylline (PTX) is a methylxanthine derivative used in a wide range of dermatoses. As well as its hemorrheologic activity, PTX has anti-inflammatory properties. Buflomedil chlorhydrate (BC) is another hemorrheological drug with peripheral vasodilatory action, whose clinical uses are similar to those of PTX. Both drugs increase intracellular levels of cAMP, either secondary to phosphodiesterase inhibition (PTX) or adenyl-cyclase stimulation (BC). Long-term cultures of normal human keratinocytes were prepared in a free-serum medium, and stimulated with 1 mg/ml of phorbol 12-myristate 13-acetate (TPA) and PTX or BC (100-1000 micrograms/ml). Levels of TNF-alpha, IL-1 alpha, IL-1 beta, IL-8 and TGF-beta 1 using ELISA and Northern blot or RT-PCR techniques were measured. TPA-induced TNF-alpha and IL-8 release from keratinocytes. TPA did not induce IL-1 alpha or IL-1 beta release of keratinocytes. TPA increased RNA expression of the TNF-alpha, IL-1 alpha, IL-1 beta, IL-8 and TGF-beta 1. BC diminished TPA-induced TNF-alpha and IL-8 release from keratinocytes; in the case of IL-8 it is possible that this inhibition occur to transcriptional level. Moreover PTX was unable to inhibit TNF-alpha and IL-8 synthesis and expression. PTX and BC reduced TPA-induced IL-1 alpha and beta expression. It is possible that BC action is specifically exerted on keratinocytes, because we did not find similar results with TNF-alpha and IL-8 synthesis in mononuclear peripheral blood cells.
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PMID:Differential modulation of IL-8 and TNF-alpha expression in human keratinocytes by buflomedil chlorhydrate and pentoxifylline. 929 91

Synovial fibroblasts from patients with osteoarthritis in culture produced parathyroid hormone-related peptide (PTHrP) on treatment with phorbol ester (TPA) in a dose- and time-dependent manner. The levels of PTHrP immunoreactivity in the conditioned medium of synovial fibroblast cultures were measured using specific PTHrP antibody. The maximum production was obtained at a concentration of 10(-8) M and 24 h after TPA treatment. But sensitivity to TPA of synovial fibroblasts differed among four patients from slight to marked. PTHrP production was also induced with inflammatory cytokines, such as 1 ng/ml of IL-1alpha, IL-1beta, IL-6 and TNF-alpha, and 10(-6) M prostaglandin E2, after 24 h treatment. The expression of PTHrP was confirmed by reverse-transcriptase polymerase chain reaction. Since the synovial fibroblasts isolated from osteoarthritic patients produce high levels of IL-6 and IL-8, typical cytokines produced in synovial fibroblasts, production of PTHrP may provide new insight into the pathophysiology of joint disorder.
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PMID:Production of parathyroid hormone-related peptide by synovial fibroblasts in human osteoarthritis. 974 21

High levels of prostaglandins are produced in human oropharyngeal carcinoma (OPC). Five human OPC cell lines tested expressed both isoforms of cyclooxygenases (COX). The pan-COX inhibitor ketorolac continuously and significantly decreased PGE(2) production and IL-6 and IL-8 levels in all OPC cell lines tested, but did not affect IL-1alpha, GM-CSF levels, or in vitro tumor cell growth. In contrast, ketorolac reduced OPC growth in vivo. The OPC cell lines used express the IL-6 receptor, and IL-6 stimulation of these cells causes transduction to occur via STAT3 pathway activation. Coincubation with OPC cell lines with conditioned medium from a TPA-exposed HL-60 cells stimulated growth proportional to the IL-6 levels measured in the conditioned medium. This growth effect was specifically inhibited by anti-IL-6 antibody. These results are consistent with cytokine products of inflammatory cells having paracrine growth effects on OPC. If chronic inflammation plays a role in promoting the development of OPC, this mechanism may also apply to other epithelial tumor systems modulated by COX activity.
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PMID:Cyclooxygenase regulates human oropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation? 1092 84


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