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)

In the present studies, the mechanisms underlying the inhibitory actions of lipocortin-1 on the pyrogenic and thermogenic properties of cytokines were investigated. Central (icv) injection of corticotropin-releasing factor (CRF, 4.7 micrograms) or the recombinant cytokines interleukin (IL)-1 alpha (50 ng), IL-1 beta (5 ng), IL-6 (20 ng), IL-8 (20 ng), or tumor necrosis factor-alpha (TNF-alpha, 1 microgram) in conscious rats produced significant increases in resting oxygen consumption (VO2, 13-26%) and colonic temperature (0.7-1.6 degrees C) within 2 h postinjection. Administration (icv) of a recombinant fragment (NH2-terminus, 1-188 amino acids) of human lipocortin-1 (1.2 micrograms) produced small increases in VO2 (< 5%) and body temperature (< 0.3 degrees C). Pretreatment (-5 min) with lipocortin-1 significantly attenuated the thermogenic and pyrogenic effects of centrally injected IL-1 beta (80% inhibition), IL-6 (60%), IL-8 (80%), or CRF (60%). However, pretreatment with lipocortin-1 failed to modify the actions of IL-1 alpha or TNF-alpha. We have previously demonstrated that the pyrogenic and thermogenic effects of IL-1 beta, IL-6, and IL-8 are dependent on the central actions of CRF, whereas IL-1 alpha and TNF-alpha act independently of CRF. Fever and thermogenesis induced by all of these cytokines (with the exception of IL-8) can also be prevented by administration of a cyclooxygenase inhibitor. The data presented here suggest that the potent antipyretic effects of lipocortin-1 may result from inhibition of the release or actions of CRF rather than modulation of eicosanoid synthesis.
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PMID:Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF. 141 82

Reactional states in leprosy are produced by different immunologic mechanisms and are responsible for a major component of tissue damage of the disease. Reversal reactions exhibit increased CD4 T cell infiltration in lesions and augmented cell-mediated immune reactivity to Ag of Mycobacterium leprae that can rapidly produce nerve damage. Erythema nodosum leprosum (ENL) reactions also have CD4 T cell infiltration but appear to be associated with the formation of immune complexes that are responsible for panniculitis, arthritis, vasculitis, and nerve injury. Because these reactional states may serve as paradigms for other types of human immunologically mediated tissue damage, this study sought to characterize the dynamic changes in cytokines associated with these reactions. Expression of cytokine mRNA in lesions of leprosy reactional states were measured by PCR. In reversal reactions, IL-1 beta, TNF-alpha, IL-2, and IFN-gamma mRNA were prominent and found to increase during the reaction, concomitant with decreases in expression of mRNA for IL-4, IL-5, and IL-10. In ENL, selective increases in the expression of IL-6, IL-8, and IL-10 mRNA was observed, with persistent expression of IL-4 and IL-5 mRNA. Reversal reactions represent naturally occurring delayed-type hypersensitivity reactions that favor macrophage activation and protective immunity, but which can engender concomitant cell injury. In contrast, ENL lesions represent immediate-type hypersensitivity reactions reflecting the selective stimulation of cytokines that attract neutrophils, stimulate antibody production, and down-regulate macrophage activation. The analysis of cytokine dynamics within different inflammatory responses can provide insights into immune mechanisms of tissue damage, and provide a useful framework for developing strategies for therapeutic intervention.
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PMID:Cytokine patterns of immunologically mediated tissue damage. 150 Jul 26

Most autoimmune diseases are HLA-associated which supports the notion that they are dependent upon specific immune activation of a limited set of T cell clones. Findings which imply that induction of autoimmune reactivity probably does not differ from normal immune responses are discussed. The possibility of transferring autoimmune disease using T cell clones indicates that target structures for auto-immune attack are also present in healthy individuals. In the present article, it is argued that autoimmune reactions and immunity against nominal conventional antigens in principle are effected and regulated by similar mechanisms. It is assumed that persistent tissue damage occurs if immune attack is directed against tissues that cannot be regenerated, such as in diabetes, or are only slowly reconstituted, such as in rheumatoid arthritis. Normal immune responses are regulated by various inflammatory mediators and cytokines/interleukins. The joint of patients with rheumatoid arthritis is discussed as a model for propagation of immune reactions and tissue destruction in autoimmune disease. Of the different cytokines which are present in the synovial fluid or produced by cells in the synovial tissue, most are presumed to have originated in macrophages/monocytes such as IL-1, IL-6, IL-8, TNF-alpha and TGF-beta. Even so, T cells are believed to have an important role for the continued reactivity associated with autoimmune disease. This discrepancy can be explained in different ways. T cell products might escape detection because they are short-lived, they are immediately consumed or they are produced only during short time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific and non-specific autoreactive immunity. 150 34

The CD4+ T cell clone HA1.7 may be made specifically nonresponsive, or anergic, to its cognate Ag, an influenza hemagglutinin peptide (HA), by pretreatment with the superantigen Staphylococcus aureus enterotoxin B or with high concentrations of HA itself. We compare the patterns of mRNA expression and protein production of selected T cell cytokines during the first 24 h after treatments that induce anergy in HA1.7 and during the same period after treatments that simulate normal cellular activation. The cytokines examined include TNF-alpha, IL-8/neutrophil activating protein-1 and the RANTES/SIS cytokines, a family of small secreted proteins with inflammatory and potential antiproliferative and leukocyte regulating activities. Messenger RNA for TNF-alpha, human MIP-1 alpha, human MIP-1 beta, and IL-8 are all induced during the development of clonal anergy in HA1.7, and these levels are significantly higher than those seen during activation of the clone using an anti-CD3 antibody and IL-2. These high levels of mRNA also persist longer than those seen after anti-CD3 and IL-2 activation. However, the increased levels of mRNA are not typically accompanied by increased protein secretion. In all cases but one, the amount of cytokine secreted by HA1.7 cells was greater after anti-CD3 and IL-2 treatments than after anergy-inducing treatments. Thus, the induction of T cell anergy in HA1.7 does not appear to require a general inhibition of T cell cytokine mRNA expression, and, in fact, anergy treatments appear to superinduce certain cytokine transcripts, but anergy-specific posttranscriptional mechanisms may exist by which cytokine release is regulated.
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PMID:Uncoupling of cytokine mRNA expression and protein secretion during the induction phase of T cell anergy. 153 Aug 60

IL-8, a cytokine known for its potent and specific neutrophil activation and chemoattractant properties, has been recently detected in the circulation during septic shock, endotoxemia, and after IL-1 alpha administration. Because of its observed in vitro actions, it has been hypothesized that IL-8 may contribute to the dynamics of circulating granulocytes and to the pathologic sequelae seen in sepsis. Here, human rIL-8 is administered to healthy nonhuman primates as a single i.v. injection or as a continuous 8-h i.v. infusion. We demonstrate that both methods of i.v. administration result in a rapid but transient, severe granulocytopenia, followed by a granulocytosis that persists as long as IL-8 levels are detectable in the circulation. There were no hemodynamic changes after IL-8 administration, and animals remained clinically stable during the 24-h observation period. No detectable circulating TNF-alpha, IL-1 beta, or IL-6 response was induced by either IL-8 administration regimen. Histopathologic examination revealed mild to moderate neutrophilic margination in lung, liver, and spleen, of greater severity in baboons receiving the 8-h infusion. There was no associated neutrophilic infiltration or tissue injury. Thus, IL-8 modulates circulating granulocyte dynamics and likely directs their actions, but when administered i.v. to healthy animals, either as a bolus dose or as a continuous infusion for up to 8 h, does not induce the hemodynamic and metabolic aberrations or the acute organ damage seen during sepsis.
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PMID:Effects of intravenous IL-8 administration in nonhuman primates. 154 15

The phospholipid platelet-activating factor (PAF) is a potent cell-derived bioactive molecule thought to be involved in diverse inflammatory processes. It has been shown that PAF can activate different leukocyte types and platelets, particularly in synergy with other agonists. In this study we examined the effect of PAF upon the release of histamine and leukotriene (LT) C4 by basophils when added alone and in combination with different agonists and cytokines. PAF by itself did neither induce histamine release nor the generation of LTC4 by basophils. However, basophils primed by the hematopoietic growth factors (hGF) IL-3, granulocyte-macrophage (GM)-CSF, or IL-5 (10 ng/ml) released preformed and de novo synthesized mediators in response to PAF at 10 to 100 nM concentrations. The extent of mediator release by hGF primed basophils in response to PAF was similar to that induced by an optimal concentration of monoclonal anti-IgE. Thus, similar to NAP-1/IL-8 and C3a, PAF efficiently stimulates mediator release in hGF-primed basophils only. However, PAF was clearly a more potent trigger of LTC4 formation in IL-3-primed cells than NAP-1/IL-8 or C3a. When PAF was used as a second trigger, the priming effect of IL-5 was less than that of IL-3 or GM-CSF, whereas the response for other IgE-independent agonists (i.e., C5a or FMLP) was augmented equally by all three hGF. IL-1 beta-pretreated basophils released minimal amounts of histamine in response to PAF. Neither TNF-alpha nor PAF, nor the combination thereof, was able to induce basophil mediator release. The efficiency of the different cytokines to prime for PAF responsiveness was strikingly similar to their capacity to enhance anti-IgE-induced mediator release. Similar to other IgE-independent agonists, the kinetic of mediator release in response to PAF was very rapid. PAF pretreatment of basophils did not enhance mediator release in response to diverse agonists, such as C5a and FMLP, in contrast to the capacity of PAF to augment the response of other leukocyte types to appropriate stimuli. Thus, depending on the presence of IL-3, GM-CSF, or IL-5, PAF is a potent basophil agonist capable of inducing histamine release as well as de novo synthesis of LTC4.
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PMID:Platelet-activating factor induces mediator release by human basophils primed with IL-3, granulocyte-macrophage colony-stimulating factor, or IL-5. 171 Oct 77

In order to better understand the factors regulating disease promotion and activity in psoriasis (PS), we searched for the in situ expression of mRNA for various cytokines in long-standing PS skin lesions. Specific hybridization with a NAP-1/IL-8 anti-sense RNA probe was keratinocyte associated and yielded strong and specific signals exclusively in the upper layers of the lesional epidermis, but not in uninvolved skin from psoriatic patients or normal skin from non-psoriatics. Interestingly, NAP-1/IL-8 transcripts were focally clustered in a spotty pattern predominantly between the tips of elongated papillae, but were absent in the lower epidermal region and the dermal compartment. We consistently failed to detect appreciable numbers of TNF-alpha and/or IL-6 mRNA-containing cells in psoriatic lesions. These results support the notion that IL-8, rather than IL-6, is an important disease-promoting cytokine in PS. In view of the known in vitro and in vivo effects of IL-8, it is conceivable that this substance greatly contributes to the major pathologic changes seen in psoriatic skin, i.e., keratinocyte hyperproliferation and leucocyte infiltration. In this case, local pharmacologic down-regulation of NAP-1/IL-8 activity could be a promising therapeutic strategy in PS.
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PMID:Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ. 171 50

Supernatants obtained from four HTLV-I transformed cell lines (MT2, MT4, C91/PL, and 81-66/45) induced in vitro migration of monocytes, polymorphonuclear leukocytes (PMN), and lymphocytes. The MT2, C91/PL, and 81-66/45 cell lines expressed both lymphotoxin (LT) and tumor necrosis factor (TNF-alpha) mRNA transcripts, and had TNF biological activity. In contrast, the MT4 cells did not express LT mRNA, had low levels of TNF-alpha transcript, and no TNF activity in the supernatant. Anti-TNF-alpha MAb, which blocks the chemotactic activity of recombinant TNF-alpha, had no inhibitory effect on the induction of migration by the MT2 and MT4 supernatants. Hence, no correlation was evident between TNF and chemotactic activity in supernatants of different HTLV-I-infected cell lines. Upon fractionation on Sephadex G50, the monocyte chemoattractant(s) eluted with two peaks in the 8-12 kD region, a size compatible with the chemotactic cytokines IL-8 and monocyte chemotactic protein (MCP). However, anti-IL-8 and anti-MCP antibodies did not have any effect, and Northern blot analysis showed that HTLV-I-transformed cell lines did not express mRNA transcripts of either IL-8 and MCP. These results demonstrate that HTLV-I transformed T-cell lines produce chemoattractant(s) active on PMN and monocytes, distinct from LT, TNF-alpha, IL-8, and MCP. Production of chemoattractants may play a role in the pathogenesis of diseases associated with HTLV-I infection.
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PMID:Chemoattractant(s) in culture supernatants of HTLV-I-Infected T-cell lines. 172 88

Injury to cartilage is a recognized sequela of neutrophil activation in arthritic joints. This study examined the possibility that chondrocytes may play a direct role in intraarticular neutrophil activation. We demonstrate that IL-1 beta-stimulated primary and subcultured human articular chondrocytes, express the gene for the potent neutrophil chemotactic and activating cytokine, IL-8. Expression of IL-8 mRNA is also inducible by TNF-alpha and LPS and, to a lesser degree, by the chondrocyte growth factor, transforming growth factor-beta, but not by platelet-derived growth factor, acidic and basic fibroblast growth factor, or epidermal growth factor. Analysis of IL-1 beta-stimulated cartilage organ cultures by in situ hybridization demonstrates that chondrocytes in all zones of cartilage are rapidly induced to express the IL-8 gene in high copy number. Metabolically labeled IL-1 beta-stimulated chondrocytes synthesize IL-8 de novo, which comigrates on SDS-PAGE with IL-8 produced by synovial fibroblasts. Furthermore, the conditioned media of IL-1 beta-stimulated chondrocytes and cartilage organ cultures contain neutrophil chemotactic activity which is completely neutralized by a specific antibody to IL-8, establishing that a bioactive form of IL-8 is the major secreted neutrophil chemotactic factor. By using a specific RIA, we demonstrate that not only IL-1 beta, but also TNF-alpha and LPS can induce abundant IL-8 secretion from chondrocytes. In conclusion, articular chondrocytes are readily inducible to express the IL-8 gene and secrete biologically active IL-8 which can promote neutrophil-mediated inflammation and cartilage destruction.
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PMID:Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. 172 66

Chemotactic cytokines play a critical role in recruiting leukocytes to sites of tissue injury. Interleukin-8 (IL-8) is a chemotactic cytokine secreted by a variety of cells (eg, monocytes, endothelial cells, fibroblasts) during the inflammatory response. In this report, the authors demonstrate that human transitional cell carcinomas and renal cell carcinomas have the capacity to elaborate IL-8 in response to the inflammatory mediators IL-1 beta and tumor necrosis factor (TNF)-alpha. All cell lines expressed high levels of IL-8 mRNA on stimulation with either IL-1 beta or TNF-alpha, but not lipopolysaccharide; one expressed the gene constitutively. The authors selected one transitional cell carcinoma cell line (UM-UC-9) and one renal cell carcinoma cell line (UM-RC-5) for further study. Both displayed a time- and dose-dependent increase in steady-state levels of IL-8 mRNA in response to IL-1 beta and TNF-alpha. Specific mRNA was detectable by 1 hour after stimulation. Secretion of antigenic IL-8 measured by enzyme-linked immunosorbent assay into culture supernatants reflected the kinetics of mRNA expression. Because heat-inactivated TNF-alpha failed to induce synthesis of IL-8 mRNA, and cycloheximide augmented TNF-alpha-induced synthesis, IL-8 expression appears to be a stimulus-specific primary induction phenomenon. As with other inflammatory mediators whose mRNA contains a 3' AU-rich sequence (eg, IL-2, TNF-alpha), the half-life of IL-8 mRNA was short, less than 1 hour. Our data suggest that secretion of IL-8 by malignant cells may partly account for the inflammatory infiltrates associated with some malignant neoplasms.
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PMID:Cytokine-induced gene expression of interleukin-8 in human transitional cell carcinomas and renal cell carcinomas. 173 30


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