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)

Resistance of cancer cells against apoptosis induced by death factors contributes to the limited efficiency of immune- and drug-induced destruction of tumors. We report here that insulin and insulin-like growth factor-I (IGF-I) fully protect HT29-D4 colon carcinoma cells from IFN-gamma/tumor necrosis factor-alpha (TNF) induced apoptosis. Survival signaling initiated by IGF-I was not dependent on the canonical survival pathway involving phosphatidylinositol 3'-kinase. In addition, neither pp70(S6K) nor protein kinase C conveyed IGF-I antiapoptotic function. Inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) with the MAPK/ERK kinase inhibitor PD098059 and MAPK/p38 with the specific inhibitor SB203580 partially reversed, in a nonadditive manner, the IGF-I survival effect. Inhibition of nuclear factor kappaB (NF-kappaB) activity by preventing degradation of the inhibitor of NF-kappaB (IkappaB-alpha) with BAY 11-7082 also blocked in part the IGF-I antiapoptotic effect. However, the complete reversal of the IGF-I effect was obtained only when NF-kappaB and either MAPK/ERK or MAPK/p38 were inhibited together. Because these pathways are also those used by TNF to signal inflammation and survival, these data point to a cross talk between IGF-I- and TNF-induced signaling. We further report that TNF-induced IL-8 production was indeed strongly enhanced upon IGF-I addition, and this effect was totally abrogated by both MAPK and NF-kappaB inhibitors. The IGF-I antiapoptotic function was stimulus-dependent because Fas- and IFN/Fas-induced apoptosis was not efficiently inhibited by IGF-I. This was correlated with the weak ability of Fas ligation to enhance IL-8 production in the presence or absence of IGF-I. These findings indicate that the antiapoptotic function of IGF-I in HT29-D4 cells is based on the enhancement of the survival pathways initiated by TNF, but not Fas, and mediated by MAPK/p38, MAPK/ERK, and NF-kappaB, which act in concert to suppress the proapoptotic signals. In agreement with this model, we show that it was possible to render HT29-D4 cells resistant to Fas-induced apoptosis provided that IGF-I and TNF receptors were activated simultaneously.
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PMID:Insulin-like growth factor-I protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor alpha-induced mitogen-activated protein kinase and nuclear factor kappaB signaling pathways. 1076 92

Keratinocytes (KC) are important source of and targets for several cytokines. Although KC express IL-15 mRNA, the functional effects of IL-15 on these epithelial cells remain to be dissected. Investigating primary human foreskin KC and HaCaT cells, we show here by semiquantitative RT-PCR and flow cytometric analysis that both translate IL-15 and IL-15R mRNA and express IL-15 and IL-15Ralpha protein on the cell surface, suggesting that human KC can employ IL-15 for juxtacrine signaling. While IL-15 exerted no significant effect on KC proliferation and IL-6 or IL-8 secretion, IL-15 inhibited both anti-Fas and methylcellulose-induced KC apoptosis in vitro. This is in line with the recognized potent anti-apoptotic effects of IL-15. IL-2, whose receptor shares two components with the IL-15R, failed to inhibit KC apoptosis. Together with the role of IL-15 in sustaining chronic immune reactions, this invited the question of whether a reduction of KC apoptosis by IL-15 may be involved in the pathogenesis of psoriasis, a chronic hyperproliferative inflammatory skin disease characterized by abnormally low KC apoptosis in the epidermis. Remarkably, compared with nonlesional psoriatic skin and skin of healthy volunteers, lesional psoriatic epidermis showed high IL-15 protein expression in the epidermis and enhanced binding activity for IL-15. Therefore, antagonizing the inhibitory effects of IL-15 on KC apoptosis deserves exploration as a novel therapeutic strategy in psoriasis management.
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PMID:Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis? 1092 12

Members of the TNF superfamily, including Fas, Fas ligand, and CD40, have been shown to be expressed on tumor cells. In the studies described in this work, we report that another family member, the ligand for 4-1BB (CD137), is expressed on various human carcinoma cell lines, on cells of solid tumors derived from these cell lines, and cells obtained from human tumors. Expression of 4-1BB ligand (4-1BBL) mRNA was detected by both RT-PCR and Northern blot analysis, and expression of 4-1BBL protein was detected by Western blot analysis of whole cell lysates and by FACS analysis of tumor cells and cell lines. Incubation of tumor cells with a 4-1BB-Ig fusion protein led to the production of IL-8 by the cells, demonstrating that the 4-1BBL is functionally active and signals back into the tumor cells. Furthermore, 4-1BBL expressed on the carcinoma cells functioned as a costimulatory molecule for the production of cytokines (most notably IFN-gamma) in cocultures of T cells and tumor cells. These findings suggest that 4-1BBL expressed on carcinoma cells may significantly influence the outcome of a T cell-tumor cell interaction.
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PMID:Constitutive expression of functional 4-1BB (CD137) ligand on carcinoma cells. 1094 24

Astrocytes exert many active roles in brain homeostasis, potentially including the regulation of immune reactions. They possess a substantial aptitude for plasticity and, indeed, functional and phenotypic changes are frequently encountered in reactive gliosis observed in brain injuries. The significance of reactive astrocytes is still poorly defined, but it is clear that these cells are an important source of cytokines in inflamed brain. How tumor necrosis factor (TNF) and TNF-receptor family members contribute to this reaction is an interesting issue that is currently being explored. It was previously shown that reactive astrocytes express high levels of Fas (CD95) and respond to Fas ligand (CD95L) by apoptosis or IL-8 production. TWEAK (Apo-3 ligand) is a recently identified member of the TNF family that is produced mainly by leukocytes that can infiltrate the inflamed brain and thus influence astrocyte behavior. Here we show that human astrocytes derived from different regions of the brain specifically bind TWEAK and are totally resistant to TWEAK mediated apoptosis. In addition, high amounts of IL-8 and IL-6 were secreted by astrocytes after TWEAK exposure. Finally, expression of cell surface molecules involved in the propagation and/or maintenance of brain inflammation was determined. TWEAK significantly increased ICAM-1 expression on astrocytes, whereas no modification was detected in the expression of Fas, TNFRI, B7-1, or MHC molecules. In conclusion, the proinflammatory effects induced by TWEAK on astrocytes in culture recapitulate many characteristics of reactive astrocytes observed in vivo, suggesting that TWEAK could play a significant role in brain inflammation.
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PMID:TWEAK stimulation of astrocytes and the proinflammatory consequences. 1097 15

Human CMV (HCMV) retinitis frequently leads to blindness in iatrogenically immunosuppressed patients and in the end stage of AIDS. Despite the general proinflammatory potential of HCMV, virus infection is associated with a rather mild cellular inflammatory response in the retina. To investigate this phenomenon, the influence of HCMV (strains AD169 or Hi91) infection on C-X-C chemokine secretion, ICAM-1 expression, and neutrophil recruitment in cultured human retinal pigment epithelial (RPE) cells was studied. Supernatants from infected cultures contained enhanced levels of IL-8 and melanoma growth-stimulating activity/Gro alpha and induced neutrophil chemotaxis compared with supernatants from uninfected RPE cells. Despite HCMV-induced ICAM-1 expression on RPE cells, binding of activated neutrophils to HCMV-infected RPE cells and subsequent transepithelial penetration were significantly reduced. Reduced neutrophil adhesion to infected RPE cells correlated with HCMV-induced up-regulation of constitutive Fas ligand (FasL) expression. Functional blocking of FasL on RPE cells with the neutralizing mAbs NOK-1 and NOK-2 or of the Fas receptor on neutrophils with mAbB-D29 prevented the HCMV-induced impairment of neutrophil/RPE interactions. Fas-FasL-dependent impairment of neutrophil binding had occurred by 10 min after neutrophil/RPE coculture without apoptotic signs. Neutrophil apoptosis was first detected after 4 h. Treatment of neutrophils with a specific inhibitor of caspase-8 suppressed apoptosis, whereas it did not prevent impaired neutrophil binding to infected RPE. The current results suggest a novel role for FasL in the RPE regulation of neutrophil binding. This may be an important feature of virus escape mechanisms and for sustaining the immune-privileged character of the retina during HCMV ocular infection.
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PMID:Decreased neutrophil adhesion to human cytomegalovirus-infected retinal pigment epithelial cells is mediated by virus-induced up-regulation of Fas ligand independent of neutrophil apoptosis. 1103 78

Interleukin-18 (IL-18) is not only a co-stimulus for the induction of interferon-gamma but also has direct proinflammatory effects by inducing tumor necrosis factor-alpha (TNF-alpha), IL-1, IL-8 and IL-6. However, the cascade of events leading to induction of cytokines by IL-18 is unclear. The aim of the present study was to investigate whether murine IL-18 stimulates production of proinflammatory cytokines, and to assess whether induction of second-wave cytokines such as IL-6 by IL-18 is driven by intermediary induction of endogenous cytokines of the TNF family or IL-1beta. When mouse peritoneal macrophages were stimulated in vitro with recombinant murine IL-18, there was a dose-dependent induction of TNF, IL-1alpha, and IL-1beta. IL-6 synthesis was also strongly induced by IL-18 and, as revealed by studies in knockout mice, this production was not dependent on interactions between endogenous cytokines of the TNF/TNF receptor family: TNF-alpha, lymphotoxin-alpha, Fas/Fas ligand (L) or CD40/CD40L. Moreover, the induction of IL-6 was also independent of endogenous IL-1beta, as macrophages isolated from IL-1beta deficient mice produced normal amounts of IL-6 after stimulation with IL-18. In conclusion, murine IL-18 has pleiotropic proinflammatory activities by inducing production of TNF-alpha, IL-1alpha, IL-1beta and IL-6, which could have important consequences for the pathophysiology of infectious and autoimmune diseases.
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PMID:Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1beta. 1106 90

Fas transduces not only apoptotic signals through various pathways but also angiogenic and proinflammatory responses in vivo. Human glioma cells express Fas although sensitivity to Fas-mediated cell death is variable, suggesting that Fas may have functions other than apoptosis in these cells. In this study, we addressed alternative functions of Fas expressed on human gliomas by Fas ligation in three human glioma cell lines, CRT-MG, U373-MG, and U87-MG, and the in vivo expression of Fas and chemokines in human glioblastoma multiforme (GBM). Herein, we demonstrate that: (a) stimulation with agonistic anti-Fas monoclonal antibody CH-11 and human recombinant soluble Fas ligand induces expression of the CC chemokine MCP-1 and the CXC chemokine interleukin-8 by human glioma cell lines at the mRNA and protein levels in a dose- and time-dependent manner; (b) selective pharmacological inhibitors of MEK1 (U0126 and PD98059) and p38 mitogen-activated protein kinase (MAPK) (SB202190) suppress Fas-mediated chemokine expression in a dose-dependent manner; (c) Fas ligation on human glioma cells leads to activation of both extracellular signal-regulated kinases ERK1/ERK2 and p38 MAPK; and (d) GBM samples express higher levels of Fas compared with normal control brain, which correlates with increased interleukin 8 expression. These findings indicate that Fas ligation on human glioma cells leads to the selective induction of chemokine expression, which involves the ERK1/ERK2 and p38 MAPK signaling pathways. Therefore, the Fas-Fas ligand system in human brain tumors may be involved not only in apoptotic processes but also in the provocation of angiogenic and proinflammatory responses.
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PMID:Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. 1130 91

Dysregulated polymorphonuclear leukocyte (PMN) apoptosis and PMN-mediated organ damage have been associated with several medical conditions such as systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), and ischemia/reperfusion injury. IL-1beta and IL-8 are two cytokines that are elevated under similar conditions. Therefore, we hypothesized that PMN exposed to these cytokines would secrete factors that could affect PMN apoptosis in a cell contact-independent manner. We have previously shown that media conditioned by IL-1beta-stimulated PMN (CM-IL1beta) for 2 h suppressed spontaneous PMN apoptosis. Data presented here demonstrate that media conditioned by IL-8-stimulated PMN (CM-IL8) also have the ability to suppress spontaneous, as well as FasL- and TNF-alpha-induced apoptosis. In contrast, CM-IL1beta was able to suppress FasL-induced, but not TNF-alpha-induced, apoptosis. To elucidate the mechanisms these media use to elicit their effects, we examined the expression and function of several apoptosis-related proteins. Experimental results demonstrate that both CM-IL1beta and CM-IL8 have the ability to delay caspase activation, but have no effect on the expression of their upstream activator, Fas, or its ligand, FasL. Examination of several Bcl-2 family members revealed a selective regulation by each media: CM-IL1beta up-regulated Bcl-X(L), while CM-IL8 down-regulated Bak expression. Additionally, CM-IL1beta, but not CM-IL8, promoted the activation of NF-kappaB, which has anti-apoptotic activity. Together, we can conclude that IL-1beta- and IL-8-stimulated PMN have the ability to suppress PMN apoptosis in a paracrine manner, and that the extent and mechanism of suppression is specific for each.
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PMID:Paracrine suppression of apoptosis by cytokine-stimulated neutrophils involves divergent regulation of NF-kappaB, Bcl-X(L), and Bak. 1179 69

Although Fas (APO-1/CD95) is expressed ubiquitously and induces cell death, it is also known to mediate other responses such as inflammation and angiogenesis in vivo. Previously, we have reported that Fas ligation induces selective expression of chemokines (IL-8 and MCP-1) in human astroglioma cells in vitro. In this study, we investigated whether Fas ligation can induce expression of other cytokines. Expression of IL-1alpha, IL-1beta, IL-6, IL-10, IL-12, IFN-beta, IFN-gamma, LT-beta, TGF-beta, TNF-a and TNF-beta mRNA levels in CRT-MG human astroglioma cells upon Fas ligation was investigated using RNase protection assay (RPA). We found that IL-6 mRNA is selectively induced upon Fas ligation, and IL-6 mRNA and protein expression was further investigated using single probe RPA and ELISA. To investigate the in vivo expression of IL-6, human brain specimens were homogenized and ELISA was performed for IL-6 expression. Herein, we demonstrate that: (1) Among these cytokines, only IL-6 was induced upon Fas ligation in a dose- and time-dependent manner; (2) A selective p38 MAP kinase inhibitor, SB202190, and a MEK inhibitor, U0126, suppressed induction of IL-6 mRNA and protein expression by Fas ligation; and (3) Glioblastoma multiforme samples (n = 11) contain significantly higher levels of IL-6 compared to those of control brains (n = 5), which correlate with increased levels of Fas. These results suggest that the Fas-FasL system may play a role in the regulation of tumor growth and survival by inducing the pleiotropic cytokine IL-6.
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PMID:Fas engagement increases expression of interleukin-6 in human glioma cells. 1194 22

We previously demonstrated that butyric acid, an extracellular metabolite from periodontopathic bacteria, induces cytotoxicity and apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we used a cell-to-cell interaction system to examine the contribution of gingival fibroblasts to the regulation of T-cell death induced by butyric acid. Butyric acid slightly suppressed fibroblast viability in a concentration-dependent fashion. However, DNA fragmentation assays indicated that butyric acid did not induce apoptosis for up to 21 h in human gingival fibroblasts (Gin 1, F41-G, and H. pulp cells). The culture supernatants were assayed for interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, IL-8, IL-11, tumor necrosis factor alpha, and transforming growth factor beta, but only the IL-6, IL-8, and IL-11 levels were significantly increased by addition of butyric acid. Butyric acid- or Fas-induced Jurkat-cell apoptosis was attenuated when Jurkat cells were cocultured with either F41-G or Gin 1 cells that had been preincubated for 6 h with butyric acid. IL-8 slightly stimulated butyric acid- or Fas-induced Jurkat-cell apoptosis in a dose-dependent manner, although a low dose of IL-8 had a mildly inhibitory effect on apoptosis. In contrast, IL-6 and IL-11 significantly suppressed butyric acid- or Fas-induced apoptosis in a dose-dependent fashion. Furthermore, the addition of monoclonal antibodies against human IL-6 and IL-11 to cocultures of gingival fibroblasts and Jurkat cells partially eliminated T-cell recovery. These results suggest that the proinflammatory cytokines such as IL-6 and IL-11, produced in fibroblasts stimulated with butyric acid, are involved in the attenuation of T-cell apoptosis by gingival fibroblasts.
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PMID:Human gingival fibroblasts rescue butyric acid-induced T-cell apoptosis. 1195 71

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