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 this work the resistance of peroxisome-proliferated hepatocytes to hydrogen peroxide (H2O2) has been studied. The question has been raised as to whether this resistance is a response to cytotoxicity. In an initial series of experiments, hepatocytes were isolated from rats that had been treated with nafenopin (NAF-hepatocytes). Isolated cells were exposed to a H2O2-generating system or to H2O2 in pulses. The ability to attach to collagen was used as a toxicological endpoint. Loss of attachment was found to be correlated to glutathione (GSH) depletion, and NAF-hepatocytes were more resistant to GSH depletion and to loss of attachment induced by H2O2 than were control hepatocytes. NAF-hepatocytes were not resistant to hydroquinone or to adriamycin. It was also indicated that this resistance was related to an altered metabolism of H2O2, less dependent on GSH. In a second series of experiments, hepatocytes from altered hepatic foci-bearing rats, treated with nafenopin or di(2-ethylhexyl)phthalate (DEHP), were used. This model was used in an attempt to monitor the development of resistance in different subpopulations of hepatocytes. It was found that the majority of hepatocytes developed resistance towards H2O2, and that, for example, foci marker-positive hepatocytes were as resistant as marker-negative cells. In control experiments with this model, it was found that marker-positive cells were more resistant towards diethyl maleate (DEM) or phorone than were marker-negative cells. In addition to demonstrating the validity of the model, these control experiments indicate an increased steady-state level of H2O2 in cells from peroxisome proliferator-treated rats. Other control experiments suggested that a low GSH-peroxidase activity protected from, rather than aggravated, the effect of peroxisome proliferation on marker-negative and GSH-depleted cells. It is concluded that H2O2 metabolism may affect the function of collagen receptors, but that a shift in H2O2 metabolism, so that it becomes less dependent on GSH, conferred resistance to this effect. The apparent non-focal induction of resistance to peroxisome proliferators, as opposed to the focal induction of resistance induced by most liver carcinogens, may explain the lack of development of gamma-glutamyltranspeptidase-positive foci in peroxisome proliferator-treated rats.
Carcinogenesis 1992 Oct
PMID:Peroxisome proliferation and resistance to hydrogen peroxide in rat hepatocytes: is development of resistance an adaptation to cytotoxicity? 142 34

Chronic inflammation of the urinary tract is a significant risk factor for the development of bladder cancer. We have shown that acute and chronic inflammation induced by intravesical instillations of killed Escherichia coli strikingly enhances N-methyl-N-nitrosourea (MNU)-initiated rat bladder carcinogenesis. To test the hypothesis that cytokines released during inflammation may be involved in the enhancement of bladder carcinogenesis, we conducted an in vitro experiment. Using soft agar growth as an index of transformation, we examined the effect of inflammation-associated cytokines on the enhancement of MNU-initiated transformation of MYP3 cells, an anchorage-dependent nontumorigenic rat bladder epithelial cell line. In the first experiment, after 1-h exposure to MNU (50 micrograms/ml), cells (5 x 10(4)) were grown in soft agar in the presence of interleukin (IL)-1 alpha, IL-6, IL-8, or tumor necrosis factor-alpha (10 to 100 ng/ml). Colonies consisting of more than 20 cells were counted 4 weeks later. Among the cytokines tested, IL-6 (100 ng/ml) significantly increased colony counts over those for the untreated controls (P < 0.001). In the second experiment, the cells treated with MNU similarly as in the first experiment were cultured with or without IL-6 (100 ng/ml) for 1 week before the cells (5 x 10(4)) were grown in soft agar in the presence or absence of IL-6. IL-6 pretreatment increased colony counts irrespective of subsequent IL-6 treatment (P < 0.05). Moreover, IL-6-stimulated anchorage-dependent growth of MNU transformants far exceeded that of the parental MYP3. However, among the transformants, there was no parallel relationship in response to IL-6 between anchorage-dependent and -independent growth. Our results suggest that IL-6 may provide a selective growth advantage to MNU-initiated bladder epithelial cells in vitro and that it may be a factor accounting for the marked enhancement of inflammation-associated rat bladder carcinogenesis.
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PMID:Enhancement of transformation in vitro of a nontumorigenic rat urothelial cell line by interleukin 6. 755 33

In the last decade, new information was achieved on mast cells (MC). Their origin is assumed to be different from that of the basophils. There are two types of MC with differences in structure, distribution and function: conjunctival and mucosal. MCs are among the most important cells in the development of allergic inflammation through the cytokines and mediators released on the activation of the surface receptors (high-affinity receptors for IgE: Fc epsilon R1). The cytokines released by MCs, e.g., interleukin 5 (IL5), IL8, are chemoattractants for eosinophils and neutrophils, respectively. The two types of mediators released by MC-those preformed, such as histamine, tryptase, serotonin, and the newly-synthetized ones, such as prostaglandin D2 (PGD2), leukotrienes C4 (LTD4), D4 (LTD4), E4 (LTE4), induce vasodilatation, bronchoconstriction, cellular chemotaxis, increase vascular permeability. The involvement of MC in many human diseases was shown within in vivo and in vitro studies (in allergy, lung fibrosis, atherosclerosis, carcinogenesis, etc.).
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PMID:Mast cells as potent inflammatory cells. 916 16

Intracellular metabolism of chromium(VI) [Cr(VI)] may lead to oxidative stress and this may account for the ability of Cr(VI) to act as a complete carcinogen. Therefore, we examined the effects of Cr(VI) treatment on the expression of oxidative stress genes in normal human lung LL 24 cells and human lung adenocarcinoma A549 cells. RT-PCR and northern blot analyses were used to determine the steady-state mRNA levels of catalase, glutathione S-transferase, glutathione reductase, Cu/Zn- and Mn-superoxide dismutases, glutathione peroxidase, NAD(P)H:quinone oxidoreductase, heme oxygenase and interleukin 8 in control cells and cells treated with 5-200 microM of Cr(VI). We found that only expression of the heme oxygenase gene is strongly elevated under the treatment with Cr(VI), and only in normal human lung LL 24 cells. Our data showed that even in the absence of Cr(VI) treatment, the level of heme oxygenase gene expression is much higher in A549 cells than in LL 24 cells. As glutathione is believed to play a protective role in cells against different forms of oxidative stress, we studied the correlation between intracellular glutathione levels and the inducibility of the heme oxygenase gene after treatment of cells with Cr(VI). Our results demonstrate that glutathione levels are increased by 35 % of control values in LL 24 cells treated with Cr(VI). The data obtained indicate that heme oxygenase, known to be a stress-inducible gene, may be involved in cellular pathways critical to the carcinogenic activity of Cr(VI) in normal human lung cells. Intracellular glutathione levels and reactive oxygen species do not appear to be primarily responsible for the stress response, induced by Cr(VI) in the studied human cells.
Carcinogenesis 1998 Aug
PMID:Effects of Cr(VI) on the expression of the oxidative stress genes in human lung cells. 974 36

Butyrate may have paradoxical effects on epithelial cells of similar origin. This study aimed to examine the hypothesis that one mechanism that dictates a cell's response to butyrate is its state of activation. First, the responses to 24 h exposure to butyrate (1-2 mM) of normal and neoplastic human colonic epithelial cells activated by their isolation and primary culture, and of colon cancer cell lines, LIM1215 and Caco-2, were examined. In primary cultures of normal and cancer cells, butyrate had no effect on alkaline phosphatase activities but significantly suppressed urokinase receptor expression by a mean +/- SEM of 30 +/- 12% and 36 +/- 9%, respectively. Interleukin-8 secretion was suppressed by 44 +/- 7% in normal cells (P < 0.05) but was unchanged in cancer cells. In contrast, the cell lines significantly increased alkaline phosphatase activities by >50%, urokinase receptor expression >2-fold and interleukin-8 secretion >3-fold in response to butyrate. Secondly, the effect of butyrate on Caco-2 cells was examined with or without prior exposure to a specific activating stimulus [tumour necrosis factor alpha (TNF alpha)]. Interleukin-8 secretion increased by 145 +/- 23% and 132 +/- 17% on 24 h exposure to 2 mM butyrate or 0.1 microM TNF alpha alone, respectively. However, in cells pre-treated with TNF alpha, butyrate significantly inhibited secretion by 34 +/- 7% below unstimulated levels. The response to butyrate of urokinase receptor, whose expression was not stimulated by TNF alpha, was unchanged. These effects were mimicked by trichostatin A, an inhibitor of histone deacetylase, suggesting that butyrate's paradoxical effects may have been operating by the same mechanism. In conclusion, some of the paradoxical effects of butyrate do not appear to represent inherent differences between normal and transformed cells. Rather, the response may be determined by the state of activation of the cells.
Carcinogenesis 1999 Apr
PMID:Colonic epithelial cell activation and the paradoxical effects of butyrate. 1022 79

The involvement of Streptococcus bovis, an member of the human gut flora, in colorectal neoplastic diseases is an object of controversy. The aim of this study was to determine the effects of S.bovis and of antigens extracted from the bacterial cell wall on early preneoplastic changes in the intestinal tract. Adult rats received i. p. injections of azoxymethane (15 mg/kg body weight) once per week for 2 weeks. Fifteen days (week 4) after the last injection of the carcinogen, the rats received, by gavage twice per week during 5 weeks, either S.bovis (10(10) bacteria) or wall-extracted antigens (100 microg). One week after the last gavage (week 10), we found that administration of either S.bovis or of antigens from this bacterium promoted the progression of preneoplastic lesions through the increased formation of hyperproliferative aberrant colonic crypts, enhanced the expression of proliferation markers and increased the production of IL-8 in the colonic mucosa. Our study suggests that S.bovis acts as a promoter of early preneoplastic lesions in the colon of rats. The fact that bacterial wall proteins are more potent inducers of neoplastic transformation than the intact bacteria may have important implications in colon cancer prevention.
Carcinogenesis 2000 Apr
PMID:Promotion of intestinal carcinogenesis by Streptococcus bovis. 1075 12

Transforming growth factor beta (TGF-beta) plays important roles in the regulation of proliferation, differentiation, apoptosis, and carcinogenesis. To identify genes responsible for maintaining the phenotype induced by TGF-beta, we performed a retrovirus-mediated gene trap screening designed to isolate TGF-beta-responsive genes in human lung carcinoma cell line A549. After screening 249 trap lines, 21 were found to express the reporter beta-galactosidase gene in a TGF-beta-responsive manner. Interestingly, in large proportions of these trap lines, the reporter gene was responsive also to phorbol ester and was suppressed by gamma interferon. Fragments of all these trapped genes were recovered by 5'- and 3'-rapid amplification of cDNA ends (RACE), and in 15 out of 21 cases (71%), the TGF-beta responsiveness of the endogenous genes was confirmed by RNA blot hybridization. In at least five cases, the TGF-beta-induced upregulation was found to be cycloheximide resistant, suggesting the roles of the genes in the TGF-beta-induced primary responses. Sequence analyses revealed that 43% (9 of 21) of the trapped genes were novel and that the remainder included genes previously reported to be upregulated by TGF-beta, such as epidermal growth factor receptor and beta1 integrin, documenting the validity of this approach. Other known genes include the ones encoding the proteins associated with cell proliferation (ribosomal proteins S15a, hNRP/NAP-1, and lipocortin II), focal adhesions (paxillin), and transcriptional regulation (thyroid hormone receptor activator molecule 1 [TRAM-1]).
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PMID:Identification of a series of transforming growth factor beta-responsive genes by retrovirus-mediated gene trap screening. 1075 10

Interleukin-8 (IL-8) is a chemokine for neutrophils and an angiogenic factor. Human tumors that express IL-8 may exhibit intense neutrophil infiltration and increased vascularization. Mutatect cells are a murine fibrosarcoma that can be grown as subcutaneous tumors in syngeneic C57BL/6 mice. Since neutrophils are a source of cytotoxic and genotoxic species, we constructed Mutatect cell lines that constitutively express human IL-8 to explore the involvement of neutrophils in tumor biology and genetic instability. An IL-8/neo expression plasmid was stably transfected into Mutatect MC17-51 cells and clone MIL-4 was isolated. Tumors initiated with 5x10(5) MIL-4 cells grew very slowly compared with tumors from pure MC17-51 cells or from 0.5 to 4x10(5) MIL-4 cells mixed with 5x10(5) MC17-51 cells. Over 95% of cells recovered from slow-growing pure MIL-4 tumors lost the transgene as measured by loss of (i) resistance to G418, (ii) expression of IL-8 protein and (iii) IL-8-specific DNA sequences. When tumors from mixed cell types were examined, loss of the transgene did not occur; rather, IL-8 producing cells appeared to have some growth advantage. The neutrophil content of tumors (as measured by myeloperoxidase) was directly proportional to the level of IL-8 expressed at the time tumors were excised. As reported earlier, the frequency of mutations at the hypoxanthine phosphoribosyltransferase locus was also directly proportional to neutrophil content. To explain some of these biological findings, we postulate that early in development of pure MIL-4 tumors, genotoxic/cytotoxic neutrophils are attracted by IL-8, which in turn leads to loss of the transgene and to localized cytotoxicity of IL-8 producing cells. In mixed tumors, where the initial IL-8 concentration may be lower, tumors might become established more readily because fewer neutrophils may be attracted. This relatively simple experimental paradigm has revealed some of the complex biological changes that can occur as a result of IL-8 in tumors.
Carcinogenesis 2001 Feb
PMID:Constitutive expression of interleukin-8 by Mutatect cells markedly affects their tumor biology. 1118 44

Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of different tumors, including those of the colon, pancreas, lung, and head and neck. We used in situ hybridization with a digoxgenin-labeled COX-2 antisense riboprobe to assess the presence of strong or intermediate versus weak or absent COX-2 expression in specimens from 160 patients with stage I non-small cell lung cancer (NSCLC). Of these, 3 specimens had strong expression, 69 had intermediate expression of COX-2, 24 had weak expression, and 64 had no detectable COX-2. The strength of COX-2 expression was associated with a worse overall survival rate (P = 0.001) and a worse disease-free survival rate (P = 0.022). The median survival times for the strong, intermediate or weak, and null COX-2 expressors were 1.04, 5.50, and 8.54 years, respectively. Interestingly, all three specimens with strong COX-2 expression came from patients who died within 18 months. Retinoic acid receptor beta (RAR-beta) is a nuclear retinoid receptor whose expression is frequently lost in aerodigestive tract carcinogenesis. We previously demonstrated that expression of RAR-beta in stage I NSCLC indicates a poor prognosis. Retinoids have been shown to prevent induction of COX-2 by mitogens and tumor promoters. Expression of COX-2 correlated with RAR-beta expression (P = 0.053), but not with k-ras mutational status, vascular endothelial growth factor, basic fibroblast growth factor, interleukin 8 levels, or other markers of angiogenesis, invasion, and metastases. Thus, like RAR-beta positivity, COX-2 overexpression appears to portend a shorter survival among patients with early stage non-small cell lung cancer. Future studies of RAR-beta and COX-2 regulation in NSCLC should further the development of prevention and therapy interventions with retinoids and/or COX-2 antagonists in this patient population.
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PMID:Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. 1130 34

Cyclooxygenase-2 (COX-2) expression is normally tightly regulated. However, constitutive overexpression plays a key role in colon carcinogenesis. To understand the molecular nature of enhanced COX-2 expression detected in colon cancer, we examined the ability of the AU-rich element-containing (ARE-containing) 3' untranslated region (3'UTR) of COX-2 mRNA to regulate rapid mRNA decay in human colon cancer cells. In tumor cells displaying enhanced growth and tumorigenicity that is correlated with elevated COX-2, vascular endothelial growth factor (VEGF), and IL-8 protein levels, the corresponding mRNAs were transcribed constitutively and turned over slowly. The observed mRNA stabilization is owing to defective recognition of class II-type AREs present within the COX-2, VEGF, and IL-8 3'UTRs; c-myc mRNA, containing a class I ARE decayed rapidly in the same cells. Correlating with cellular defects in mRNA stability, the RNA-binding of trans-acting cellular factors was altered. In particular, we found that the RNA-stability factor HuR binds to the COX-2 ARE, and overexpression of HuR, as detected in tumors, results in elevated expression of COX-2, VEGF, and IL-8. These findings demonstrate the functional significance rapid mRNA decay plays in controlling gene expression and show that dysregulation of these trans-acting factors can lead to overexpression of COX-2 and other angiogenic proteins, as detected in neoplasia.
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PMID:Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. 1173 61


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