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)

Toxic oxygen free radicals are believed to play a role in the pathogenesis of a number of respiratory diseases. In particular, pulmonary emphysema may occur because of the oxidative impairment of alpha 1-proteinase inhibitor (alpha 1-PI). We report in vitro data on a new thiol agent, P 1507 [N-5-(thioxo-L-prolyl)-L-cysteine], obtained in a series of experiments designed in view of its therapeutic potential in these clinical conditions. We found that P 1507 at the concentration of 5 x 10(-6) M was able to almost fully abolish the PMA-triggered PMN-induced oxidative impairment of alpha 1-PI. Protection may be due to the radical scavenger ability of P 1507, that markedly reduced superoxide anion production from PMNs. We also found that P 1507 did not significantly impair other defence mechanisms of PMNs (i.e. phagocytosis, chemotaxis and bactericidal activity). The release of cytokines (TNF-alpha, IL-6 and IL-8) from monocytes was not altered in the presence of P 1507. We conclude that the compound P 1507 may be considered for treatment of clinical conditions characterized by overload of oxidants, on the basis of its ability in preventing the oxidative damage of alpha 1-PI and of a lack of unwanted inhibitory effects towards defence mechanisms of phagocytes.
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PMID:Interactions of P 1507, a new antioxidant agent, with phagocyte functions. 774 Oct 36

The subendothelial basement membrane (BM) is regarded as an important barrier to the entry of leucocytes into inflammatory sites. This study compares the ability of leucocytes, platelets and endothelial cells (EC) to degrade a [35SO4]-labelled subendothelial extracellular matrix (ECM) and assesses the effect of PMA and various pro-inflammatory cytokines on this degradative activity. The different products of degradation, identified by fast protein liquid chromatography (FPLC) gel filtration chromatography, were indicative of protease, endoglycosidase (heparanase) and exoglycosidase and/or sulfatase activity. In terms of ECM degradation, EC and platelets were the most active, with PMA stimulation further enhancing the degradative activity of these two cell types. Platelets exhibited predominantly heparanase activity whereas the EC degradation products suggested a range of enzymic activities, namely proteases, heparanases and sulfatases. Interestingly, EC in suspension expressed these three enzymic activities whereas confluent EC monolayers only exhibited sulfatase activity, suggesting that the former situation might represent an angiogenic response. In the case of leucocytes, neutrophils and lymphocytes degraded the ECM to a much greater extent than monocytes. Each cell type also differed in the predominant enzymic activities it expressed, for example, heparanase activity by lymphocytes, protease activity by neutrophils and sulfatase activity by monocytes. Furthermore, PMA stimulation was shown to have differential effects on these enzymic activities. Some pro-inflammatory cytokines were found to be cell-type specific in their effects on ECM degradation. Thus, IL-1 + TNF enhanced neutrophil and EC degradation of the ECM but inhibited lymphocyte ECM degradation. In contrast, the chemokine IL-8 enhanced ECM degradation by neutrophils, lymphocytes and EC. Of particular interest was the unique sulfatase activity expressed by EC and monocytes which was induced in EC by TNF + IL-1 and IL-8, whereas in monocytes the sulfatase activity was exclusively induced by the chemokine monocyte chemotactic and activating factor (MCAF). Collectively, the results of this study show that leucocytes differ markedly in the enzymes they express to degrade the BM during extravasation and that PMA and cytokines are cell-type specific in their induction of hydrolytic enzyme activity. These results also indicate that EC may play an important role, not only in the recruitment of leucocytes, but also via sulfatase activity in the preparation of vascular BM for leucocyte extravasion.
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PMID:Comparative analysis of the ability of leucocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: evidence for cytokine dependence and detection of a novel sulfatase. 779 31

A newly synthesized demethylpodophyllotoxin derivative, 4-O-butanoyl-4'-demethylpodophyllotoxin (BDPT) or BN58705, has recently been shown to exert a potent cytotoxic activity in vitro against a variety of drug-resistant human tumor cell lines. The effect of this agent on effector cells of the immune system, however, has not been examined. The present study investigated the effect of BDPT on the response of activated human peripheral blood derived monocytes (PBM) to secrete cytokines. Activation of PBM overnight with LPS, IFN-gamma, or PMA resulted in secretion into the supernatant of TNF-alpha, IL-1 beta, IL-6, and IL-8 as assessed by ELISA. The addition of BDPT to the stimulated cultures resulted in significant inhibition of TNF-alpha and IL-1 beta secretion, whereas the secretion of IL-6 and IL-8 was not affected. The selective inhibition of TNF-alpha and IL-1 beta secretion by BDPT-treated PBM was observed with all three stimuli tested. The inhibitory effect mediated by BDPT was concentration dependent and was optimal at 6-20 microM. Time kinetic analysis indicated that the inhibition of secretion was rapid and detected as soon as 2 hr following stimulation of the PBM and lasted for as long as 24 hr. A comparison was made between BDPT and pentoxyfilline, a xanthine-derived phosphodisterase inhibitor that was reported to inhibit TNF-alpha and IL-1 beta secretion by PBM. Both BDPT and PTX showed similar time kinetics and patterns of inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion but not IL-6 from activated human peripheral blood monocytes by a new synthetic demethylpodophyllotoxin derivative. 781 57

HuGRO, IL-8 and gamma-IP-10 belong to a recently described superfamily of genes encoding a group of cytokines with inflammatory, growth regulating and/or leukocyte chemotactic properties (chemokines). We studied huGRO, IL-8 and gamma-IP-10 gene expression in unstimulated and stimulated (TNF alpha, INF gamma, TNF alpha + IFN gamma, IL-1 beta, PMA and LPS) normal human keratinocytes by Northern blot analysis. The mRNA for none of the three chemokines was detectable in unstimulated keratinocytes, but considerably elevated levels of huGRO and IL-8 mRNA, but not of gamma-IP-10 mRNA, were found in the presence of cycloheximide, indicating that huGRO and IL-8 mRNA, but not gamma-IP-10 mRNA, are constitutively produced. gamma-IP-10 mRNA was exclusively induced by IFN gamma, with a strong and transient rise between 8 and 18 h, and superinduced by the combination of IFN gamma and TNF alpha, indicating marked synergism. Both huGRO and IL-8 mRNA were induced by TNF alpha and PMA (a strong and transient rise between 2 and 8 h), but not by IFN gamma or LPS. The combination of TNF alpha and IFN gamma did not show a synergistic effect. In addition, IL-1 beta transiently upregulated huGRO mRNA but failed to induce IL-8 mRNA. Using specific oligonucleotides for alpha, beta and gamma huGRO, TNF alpha was found to induce all three forms, alpha and beta to an equal extent and gamma to a lesser extent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human growth factor (huGRO), interleukin-8 (IL-8) and interferon-gamma-inducible protein (gamma-IP-10) gene expression in cultured normal human keratinocytes. 786 61

This thesis discusses the phenotypic characteristics of different inflammatory dermatological diseases and sets this into context with the specific chemotactic ability of different cytokines. It further discusses the biological properties of different chemotactic cytokines and their relevance in certain inflammatory diseases. The term chemotaxis was introduced in 1884 by Pfeffer, who described it as directional migration of leukocytes along a gradient. Regular studies of chemotaxis were, however, not possible until 1962 when Boyden developed the chemotaxis chamber technique. This test has since then been improved, and it is now possible to define and characterize chemoattractants and examine the special chemotactic behavior of leukocytes. We investigated T lymphocyte responses towards different chemoattractants using a modified Boyden chamber technique and found that approximately 50% of normal individuals have cells which respond whereas T-cells from the remaining persons did not respond. We therefore chose human T lymphocytic cell lines as target cells for chemotaxis screening to avoid inter-individual variations among donors. T lymphocytic infiltrates dominated by CD4+, CD45R0+ memory T cells are characteristic for many dermatological inflammatory diseases. We have therefore performed experiments to evaluate whether an earlier described epidermal lymphocyte chemotactic factor (ELCF) from skin overlying a tuberculin skin reaction in addition with other cytokines specifically attracts different subsets of lymphocytes. ELCF which probably reflects a mixture of different epidermal T lymphocyte chemotactic factors rather than a single factor was shown to specifically attract CD4+, CD45R0+ T lymphocytes in contrast to fMLP, IL-8, C5a and LTB4, which induced equal chemotaxis for both CD4+ and CD8+ T lymphocytes. A newly described inhibitory cytokine IL-10 selectively attracted the CD8+ subpopulation of T lymphocytes, and it is suggested that IL-10 could be an important factor in the downregulation of an inflammatory response. The recently discovered neutrophil chemotactic and activating factor IL-8 has been shown to be chemotactic for T lymphocytes as well. It belongs to a family of 8,000-10,000 KDa peptides of which a monocyte chemotactic and activating factor MCAF is also a member. We showed that mRNA for IL-8 could be expressed in highly purified T lymphocytes only upon stimulation with ionomycin and PHA or PMA and PHA, and to a lesser extent PMA and IL-2. This is consistent with other reports of T lymphocytes requiring two signals for cytokine production. We showed that it was only the CD4+ subpopulation of the T lymphocytes that expressed IL-8 mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemotactic cytokines and inflammation. Biological properties of the lymphocyte and monocyte chemotactic factors ELCF, MCAF and IL-8. 790 57

Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease, helps to protect the epithelial surface of the airways from the destructive capacity of neutrophil elastase. Based on the recognition that SLPI levels can increase in the presence of airway inflammation, we hypothesized that inflammatory stimuli should modulate the expression of the SLPI gene in airway epithelial cells. To evaluate this, the modulation of SLPI gene expression with various inflammatory stimuli was evaluated in the HS-24 human bronchial epithelial cell line. After preliminary studies showed that several inflammatory mediators enhanced SLPI messenger RNA (mRNA) levels, PMA was used as a model inflammatory stimulus. PMA significantly increased the level of 0.7-kb SLPI mRNA transcripts in HS-24 cells in a dose- and time-dependent fashion and increased the amount of SLPI protein in the culture supernatant. Nuclear run-on analyses showed that the SLPI gene transcription rate increased approximately twofold after PMA stimulation. Transfection studies using fusion genes composed of fragments of up to 1.2 kb of the 5' flanking sequence of the SLPI gene and a luciferase reporter gene demonstrated potent promoter activity in the 131-bp segment (-115 to +16 relative to the transcription start site), and all longer segments up to 1.2 kb, whereas smaller segments showed low promoter activity. An 18-bp element (-98 to -115), in a region with homology to PMA-responsive regions in the Moloney murine leukemia virus enhancer and the IL-8 gene, was shown to be of importance in the level of transcription of the SLPI gene. However, this element was not responsible for the upregulation of SLPI gene expression by PMA. Evaluation of HS-24 cells in the presence of actinomycin D demonstrated that SLPI mRNA transcripts were very stable and became more so in the presence of PMA. Thus, SLPI gene expression in airway epithelial cells can be upregulated by an inflammatory stimulus, and this modulation is regulated at both the transcriptional and posttranscriptional levels. These mechanisms of SLPI upregulation likely play a role in defending the epithelial surface in the local milieu of inflammatory lung diseases.
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PMID:Modulation of secretory leukoprotease inhibitor gene expression in human bronchial epithelial cells by phorbol ester. 791 12

Human autologous tumor-specific T-helper 2 (Th2) cells were investigated in melanoma tumor-infiltrating lymphocytes (TILs). Both a CD4+ T-cell line and its 5 potential T-cell clones established from TILs of a patient with metastatic melanoma produced significant levels of IL-4, IL-6, IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to autologous, but not any of 12 allogeneic, melanoma cell lines. They also produced IL-3 and IL-8 but not IL-2, IFN-gamma, TNF-alpha or TNF-beta in response to autologous tumor cells. Furthermore, they showed autologous melanoma-specific cytotoxicity only in an 18-hr 51Cr-release assay. Specific IL-4, IL-6 or IL-10 production by the CD4+ M73 T-cell line and its clone was inhibited by anti-class II DR (but not anti-class I) MAb, whereas their specific cytotoxicity was inhibited by anti-class I (but not anti-class II) MAb. Anti-CD3 and -CD4 MAb (but not anti-CD8) abrogated both IL-4, IL6 and IL-10 production and cytotoxicity, while anti-IL-4 antibody did not inhibit cytotoxicity. CD4+ potential T-cell clones, but not CD8+ clones, that were established from freshly isolated TILs without in vitro sensitization by autologous tumor cells also produced IL-4, IL-6 and IL-10 but not IFN-gamma or tumor necrosis factor (TNF) alpha in an autologous tumor-specific fashion. These Th2 cells were neither reactive to EBV-B cells nor suppressive against CD8+ T-cell clones. PMA and PHA stimulated these potential T-cell clones, regardless of their specific lymphokine production, to produce IL-3, IL-4, IL-6, IL-8, IL-10, GM-CSF, TNF alpha and IFN-gamma. Our results demonstrate the presence of autologous tumor-specific Th2 cells at the melanoma sites.
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PMID:Characterization of autologous tumor-specific T-helper 2 cells in tumor-infiltrating lymphocytes from a patient with metastatic melanoma. 791 81

Etretinate has proven to be effective in the treatment of psoriasis. Since abnormal proliferation and cytokine secretion are well-known features of psoriatic epidermis, we studied the in vitro effects of etretinate on these two processes using human keratinocytes. Etretinate promoted proliferation of normal human keratinocytes (NHKs) grown in keratinocyte growth medium (KGM) but not in growth factor-deficient keratinocyte basic medium (KBM). Moreover, etretinate partly overcame growth inhibition by PMA. Etretinate was shown to have an effect on either IL-1 alpha or IL-8 secretion in unstimulated NHKs. In HSC-1, a human squamous cell carcinoma cell line cultured in 20% FCS/DMEM, inhibited IL-1 alpha secretion and enhanced IL-8 secretion. These results indicate that the effects of etretinate on keratinocyte proliferation and cytokine secretion may depend on cell type and culture conditions. Stimulation of NHKs with PMA significantly enhanced IL-1 alpha and IL-8 secretion, and these effects were inhibited by etretinate. However, etretinate failed to inhibit rTNF alpha-induced IL-8 secretion, suggesting that etretinate regulation of NHK cytokine secretion may also depend on the stimulus. As treatment of keratinocytes or epidermis with PMA can induce psoriasis-like changes, so might the experimental "anti-PMA" activity of etretinate be related to its therapeutic benefit in the treatment of psoriasis.
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PMID:Effects of etretinate on keratinocyte proliferation and secretion of interleukin-1 alpha (IL-1 alpha) and IL-8. 796 65

The formylpeptide (fMLP) and C5a chemoattractants were previously shown to cross-desensitize each other's ability to mobilize Ca2+ in leukocytes but not to affect nonchemoattractant Ca(2+)-mobilizing receptors, and vice versa. Our data show that all receptors studied underwent homologous desensitization. Interestingly, peptide chemoattractants (fMLP, C5a, and IL-8) desensitized each other's Ca(2+)-mobilizing responses, but had no effect on a Ca(2+)-mobilizing purinergic receptor. Lipid chemoattractant receptors (PAF and leukotriene B4) were also desensitized by peptide chemoattractants but not vice versa. In the presence of cytochalasin B, only fMLP and C5a caused the activation of phospholipase D in intact leukocytes and enhanced desensitization of IL-8 and C5a but not fMLP receptors. To measure receptor/G protein interactions, agonist-stimulated GTP gamma S binding to leukocyte membranes was measured. Whereas all peptide receptors underwent homologous desensitization, C5a and IL-8, but not fMLP, receptors were cross-desensitized by other peptide chemoattractants. Furthermore, PMA caused inhibition of C5a- and IL-8- but not fMLP-stimulated GTP gamma S binding. These data suggest that in addition to homologous desensitization, peptide chemoattractant receptors cross-desensitize one another by at least two processes. One can be detected at the level of receptor/G-protein interaction and possibly involves receptor phosphorylation by protein kinase C. The fMLP receptor is resistant to this process. The second process is distal to receptor/G-protein interaction and utilizes an undefined pathway to cross-desensitize the Ca2+ mobilization response to all peptide chemoattractants. We propose that receptor cross-desensitization in leukocytes is orchestrated at several levels by mechanisms with selectivity for types of chemoattractant receptors.
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PMID:Cross-desensitization of receptors for peptide chemoattractants. Characterization of a new form of leukocyte regulation. 808 98

Human neutrophils were exposed to the chemotactic factors C5a, FMLP, IL-8, leukotriene B4, and PAF, for 30 s, and subsequently analyzed for protein tyrosine phosphorylation by immunoblotting whole cell lysates with a polyclonal antiphosphotyrosine Ab. All chemotactic factors caused the rapid de novo tyrosine phosphorylation of a broad band of approximately 120 kDa and increased the phosphotyrosine content of several other proteins, including two with molecular masses of 60 and 56 kDa that were present in the unstimulated neutrophil. Tyrosine phosphorylation was evident as early as 10 s after stimulation and was maintained for 1 to 3 min before dephosphorylation occurred. The extent of tyrosine phosphorylation was dependent on the concentration of chemotactic factor, with stimulation observed at concentrations as low as 10 to 100 nM. To investigate the pathway used by chemotactic factors to transduce this signal, neutrophils were treated with PMA. PMA also stimulated tyrosine phosphorylation in the neutrophil but with a slower response time and a different pattern of affected proteins. Additional experiments suggested that tyrosine phosphorylation is involved in the regulation of the neutrophil respiratory burst because the tyrosine kinase inhibitor, herbimycin A, inhibited C5a-induced protein tyrosine phosphorylation and also prevented C5a- and FMLP-induced superoxide anion production. Herbimycin A also inhibited PMA-induced tyrosine phosphorylation and superoxide anion production. To confirm that the ability to stimulate tyrosine phosphorylation was intrinsic to the C5a receptor, tyrosine phosphorylation was examined in both undifferentiated U937 cells (C5a receptor negative) and cAMP differentiated U937 cells (C5a receptor positive). C5a induced tyrosine phosphorylation only in differentiated U937 cells. Analysis of the C5a receptor mRNA using the PCR confirmed its presence in differentiated and its absence in undifferentiated U937 cells. Therefore, C5a stimulates tyrosine phosphorylation via a receptor-mediated mechanism and U937 cells provide a system in which G-coupled receptor-mediated tyrosine phosphorylation can be investigated.
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PMID:C5a as a model for chemotactic factor-stimulated tyrosine phosphorylation in the human neutrophil. 813 59


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