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)

Situated in secretory granules of cytotoxic cells, granzymes are essential for induction of target cell apoptosis with perforin. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independently of their role in the lytic event. Thrombin has been shown to function as an activation molecule by cleaving its receptor. We hypothesize that granzymes may act similarly. In this report, we show that purified human granzyme A can induce human lung fibroblasts to produce IL6 and IL8. Cytokine induction is abrogated by treating the serine protease with the suicide serine protease inhibitor 3,4-dichloroisocoumarin. Other fibroblast lines as well as epithelial cells produced cytokines in response to granzyme A. Our data suggest that granzyme A can function as an activation molecule with potentially important immunoregulatory functions.
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PMID:Extracellular Activities of Human Granzymes 866 Aug 52

Situated in secretory granules of cytotoxic cells, granzymes are essential for induction of target cell apoptosis with perforin. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independently of their role in the lytic event. Thrombin has been shown to function as an activation molecule by cleaving its receptor. We hypothesize that granzymes may act similarly. In this report, we show that purified human granzyme A can induce human lung fibroblasts to produce IL6 and IL8. Cytokine induction is abrogated by treating the serine protease with the suicide serine protease inhibitor 3,4-dichloroisocoumarin. Other fibroblast lines as well as epithelial cells produced cytokines in response to granzyme A. Our data suggest that granzyme A can function as an activation molecule with potentially important immunoregulatory functions.
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PMID:Extracellular activities of human granzymes. I. Granzyme A induces IL6 and IL8 production in fibroblast and epithelial cell lines. 875 61

Procedures to diagnose renal allograft rejection depend upon detection of graft dysfunction and the presence of a mononuclear leukocytic infiltrate; however, the presence of a modest cellular infiltrate is often not conclusive and can be detected in non-rejecting grafts. We have pursued a molecular approach utilizing reverse transcription (RT)-PCR to test the diagnostic accuracy of multiple immune activation gene analysis as means to diagnose renal allograft rejection. The magnitude of intragraft gene expression of 15 immune activation genes was quantified by competitive RT-PCR in 60 renal allograft core biopsies obtained for surveillance or to diagnose the etiology of graft dysfunction. Results were compared with a clinicopathological analysis based upon the histological diagnosis (Banff criteria) and the response to antirejection treatment. During acute renal allograft rejection intragraft expression of the interleukin (IL)-7 (P < 0.001), IL-10 (P < 0.0001), IL-15 (P < 0.0001), Fas ligand (P < 0.0001), perforin (P < 0.0001), and granzyme B (P < 0.0015), but not IL-2, interferon gamma, or IL-4, genes is significantly heightened. Amplified RANTES and IL-8 gene transcripts are sensitive but nonspecific markers of rejection. A simultaneous RT-PCR evaluation of perforin, granzyme B, and Fas ligand identifies acute rejection, including cases with mild infiltration, with extraordinary sensitivity (100%) and specificity (100%). Effective antirejection therapy results in a rapid down-regulation of gene expression. The combined analysis of Fas ligand, perforin, and granzyme B gene expression by quantitative RT-PCR provides a reliable tool for diagnosis and follow-up of acute renal allograft rejection. Its accuracy and a potential rapid application within few hours suggest its use in the clinical management of renal transplant patients.
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PMID:Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation. 901 47

Leprosy patients during the natural course of the disease may develop reactional episodes, namely reversal reaction (RR) and erythema nodosum leprosum (ENL). Immunological events described as occurring during RR indicate up-regulation of the immune response, whereas in ENL the events are not fully understood. The aim of this study was to analyse the in vivo pattern of cytokine gene expression in the reactional states of leprosy. Peripheral blood mononuclear cells (PBMC, n = 14) and tissue samples (n = 17) obtained from patients with ENL and RR were obtained and assayed by RT-PCR. PBMC obtained from unreactional patients (n = 15) and normal individuals (n = 5) were also assessed. Expression of interferon (IFN)gamma, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-2Rp55, perforin and IL-1beta mRNA in PBMC were detected mostly in ENL/RR patients, but not in unreactional patients. Likewise, cytokines such as IL-6, IL-8, tumour necrosis factor (TNF)alpha and TNFbeta were also present in reactional and tuberculoid patients as opposed to lepromatous leprosy (BL/LL). Interestingly, the majority of ENL/RR patients showed messages for IL-6, IL-10, IL-12 and TNFalpha in the skin. IFNgamma was detected in 84.6% (ENL) and 100% (RR) of the patients, whereas IL-4 was detected only in few individuals (38.5 and 25%, respectively). Although mRNA expression and protein levels may be different, the data reported in this study suggest a cytokine mRNA profile that seems to be indistinguishable for RR and ENL. In addition, it shows up-regulation of immuno-inflammatory cytokines in the blood and tissue of the same patient examined before and during reaction. Furthermore, it is suggested that this pattern of response results from an immunological reactivation that might lead to an acute inflammatory response in both reactional episodes.
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PMID:Cytokine mRNA expression in leprosy: a possible role for interferon-gamma and interleukin-12 in reactions (RR and ENL). 1056 58

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.
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PMID:Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules. 1060 13

Accumulation and activation of inflammatory cells in the lung characterize the acute respiratory distress syndrome (ARDS). However, the precise mechanism for lung epithelial and endothelial cell damage remains unknown. Based on evidence that rapid apoptosis caused by CD8(+) cytolytic T cells can induce pathological cell death, we hypothesized that this mechanism may also participate in the acute lung injury, and attempted to evaluate apoptosis-related factors in bronchoalveolar lavage fluid (BALF) from ARDS patients. Quantitative polymerase chain reaction (PCR) analysis revealed that the messenger ribonucleic acids (mRNAs) for several apoptosis molecules, such as perforin, granzyme A, granzyme B, FasL, and Fas were highly upregulated in the acute phase of ARDS following sepsis. In contrast, low or negligible mRNA expression of these molecules was detected in patients with normal lung function, in septic patients without lung injury (septic non-ARDS), and in patients in the late phase of septic ARDS (late ARDS). While the genes of the classic proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8, and inducible nitric oxide synthase (iNOS) were upregulated in septic non-ARDS or late ARDS patients, expressions of these genes in the acute phase of septic ARDS were most distinct. The immunofluorescence flow cytometry showed that only the lymphocyte population in BALF from acute phase of septic ARDS patients expressed perforin and granzyme. The level of soluble FasL in the BALF increased only in the acute ARDS patients. These results thus suggested that the dual apoptosis pathway, perforin/granzyme and FasL/Fas system, is likely to be another participant for the pathogenesis of acute lung injury.
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PMID:Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. 1137 24

Most gene expression methods often involve cumbersome steps or use expensive facilities. Additionally, some of the techniques, such as cDNA biochip, cannot define the sub-population of tissue from which the amplified cDNA was made. Here we present a rapid and high throughput screening method for analyzing the pattern of gene expression of tumor-infiltrating lymphocyte (TIL), which can minimize manipulations in cloned DNA sequencing and in bioinformatics. The pattern of TIL gene expression was studied in one ovarian cancer and one liver cancer. Our results have demonstrated that TILs have three different gene expression profiles: the first set of genes is involved in cell proliferation and mitogenic stimulation, such as c-myc and IL-8, LD78, MIP-1beta, insulin-induced protein and AH-receptor; the second set of genes includes those involved in attachment of lymphocytes to endothelium and extravasation into tumor tissues such as P-selectin ligand and integrin; and the third set, which includes genes such as the perforin, FAS ligand and granzyme B, is related to cytotoxic function to tumor cells. The patterns of TIL gene expression obtained from two specimens are marginally different and can be used in explaining the basis of molecular mechanisms regulating cellular interactions and cytotoxicity.
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PMID:Identification of mRNAs expressed in tumor-infiltrating lymphocytes by a strategy for rapid and high throughput screening. 1102 87

The spontaneous loss of normal karyotype embryos may be initiated or prevented by the maternal immune system. In mice, loss between the time of implantation (day 4.5) and formation of a vascularized placenta (day 9.5) when the embryo is too large to survive by diffusion alone, is analogous to occult pregnancy failure in humans. They are called occult because usually the woman does not know she is pregnant. From studies in mice, these early losses have a different mechanism than abortion of a vascularized placenta (analogous to clinically evident human spontaneous miscarriage). The latter depend on the activation of the novel prothrombinase fgl2 on the fetal trophoblast and in maternal decidua by the T helper-1 (Th1) type cytokines TNF- alpha+gamma -interferon that arise from NK cells and NK gammadelta T cells; conversion of prothrombin to thrombin which in turn generates IL8 that activates polymorphonuclear leukocytes leads to embryonic death. These inflammatory processes are counteracted by Th2/3-type cytokines that arise in part from V gamma 1 delta 6 T cells reacting to, as yet, unidentified trophoblast antigens in the presence of the 'tolerance signaling molecule' OX-2. By contrast, peri-implantation losses (between implantation and formation of a vascularized placenta, analogous to occult losses in humans) appear to be dependent upon perforin(+)cells, complement activation, and products of alphabeta T and NK alphabeta T cells, but not on TNF- alpha or procoagulant activation. Similarities and differences between findings in the mouse and human, and the potential evolutionary significance of mechanisms affecting reproductive success are reviewed.
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PMID:Procoagulants in fetus rejection: the role of the OX-2 (CD200) tolerance signal. 1143 33

Streptolysin O (SLO), archetype of a cholesterol-binding bacterial cytolysin, forms large pores in the plasma membrane of mammalian cells. We have recently reported that when a limited number of pores are generated in a cell, they can be sealed in a Ca++-dependent process. Here, we show that resealing is followed by the release of IL-6 and IL-8 from keratinocytes and from endothelial cells, both relevant targets for SLO attack. Production of cytokines by these cells was preceded by activation of transcription factor nuclear factor kappaB, which thus emerges as a common denominator of stress responses to various pore-forming agents, including alpha-toxin of Staphylococcus aureus and complement. Furthermore, we show that activation and cytokine release in response to an agent that forms a pore in the plasma membrane do not depend on paracrine effects, because supernatants of cells perforated by SLO did not activate bystander cells. The study provides definitive evidence that a transient transmembrane pore suffices to trigger productive transcriptional activation in a target cell.
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PMID:Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events. 1174 25

Pneumonia and lung injury are hallmarks of early-onset neonatal group B streptococcal (GBS) infections. Production of a beta-hemolysin/cytolysin (beta-h/c) encoded by the cylE gene is associated with GBS virulence in vivo. To elucidate the contribution of the beta-h/c toxin to lung injury, the interactions of GBS wild-type strains and isogenic cylE mutants with A549 lung epithelial cells were examined. Compared with wild-type GBS strains, cylE mutants did not produce cytolytic injury, even at high inocula, and exhibited decreased cellular invasion. Additionally, cylE mutants induced less A549 cell release of the neutrophil chemoattractant interleukin (IL)-8. GBS invasion and IL-8 induction were significantly reduced in the presence of dipalmotyl phosphatidylcholine, a major constituent of lung surfactant and a known inhibitor of beta-h/c activity. These data indicate that the GBS beta-h/c contributes to invasion and immune activation of lung epithelial cells and may represent a multifunctional virulence factor in the early pulmonary stages of GBS infection.
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PMID:Group B streptococcal beta-hemolysin/cytolysin promotes invasion of human lung epithelial cells and the release of interleukin-8. 1180 93


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