Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates immune responses and acute phase reactions. It has demonstrated a growth factor function in several tumors, including those of salivary, plasma cell, and renal origin. We performed immunohistochemical staining for IL-6 localization on 57 salivary tumors. Reactivity was scored by intensity (0 to 4+) and percentage of cells staining, and the tumors were classified into three groups representing low (0 to 1+, 0% to 30%), moderate (2 to 3+, 31% to 75%), or high (> 3 to 4+, 76% to 100%) reactors. High reactivity was found in all primary pleomorphic adenomas (N = 10), five of eight recurrent pleomorphic adenomas, and all polymorphous low grade adenocarcinomas (N = 4). Moderate reactivity was observed in four of seven basal cell adenomas and three of five myoepitheliomas. Low reactivity characterized all acinic cell carcinomas (N = 3) and mucoepidermoid carcinomas (N = 3) as well as six of nine primary adenoid cystic carcinomas and all metastatic adenoid cystic carcinomas (N = 3). Carcinoma ex pleomorphic adenoma (N = 5) had three low and two moderate reactors. A pattern emerged in which the benign and low grade malignant tumors showed stronger reactivity than the metastatic or high grade malignant tumors. This suggests an inverse relationship between the presence of IL-6 and the biological aggressiveness of salivary gland tumors. The function of IL-6 in salivary gland neoplasia awaits further study and elucidation.
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PMID:Immunolocalization of interleukin-6 in salivary gland tumors. 753 83

It has been reported that a high plasmatic concentration of interleukin-6 (IL-6) is correlated to a lack of response to immunotherapy in several malignancies, suggesting that IL-6 was either a marker of tumour aggressiveness or had only a predictive value of response to immunotherapy. To discriminate between these two possibilities, a retrospective study was performed in a series of 19 patients with metastatic renal cell carcinoma who did not respond to IL-2/IFNalpha/5-FU treatment. Serum levels of IL-6, C-reactive Protein (CRP), soluble IL-2-receptor (sIL-2R), M-CSF and neopterin were assayed before treatment. IL-6 showed a significant correlation with patients median survival time (P < 0.016), suggesting that serum concentration of IL-6 before treatment is a marker of tumour aggressiveness rather than a predictive parameter for an immunological response.
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PMID:IL-6 is a survival prognostic factor in renal cell carcinoma. 927 23

Cytokines appear to play an important role in the development and progression of epithelial tumors. Cultured normal human thyroid follicular cells constitutively release high levels of interleukin-6 (IL-6) and IL-8, together with low to moderate levels of transforming growth factor-alpha (TGF-alpha) and TGF-beta. IL-6 appears to play multiple functions in thyroid physiology and disease. Because certain data indicate an inverse relationship between IL-6 production and epithelial tumor aggressiveness, we used both tissue culture methods and histochemical techniques to search for possible alterations of cytokine expression in thyroid carcinomas. As compared to cultures from normal tissue and well-differentiated carcinoma, production of IL-6 was strongly down-regulated in cultures derived from undifferentiated carcinoma. In contrast, levels of IL-8, TGF-alpha, and TGF-beta produced by neoplastic TFC were similar to those produced by normal cells. Actually, production of TGF-alpha was slightly enhanced in cultures from well-differentiated carcinoma. Immunoassay results were confirmed by reverse transcriptase-PCR analysis. Immunohistochemistry of human thyroid carcinomas (n = 99) and normal thyroid tissue (n = 85) showed that immunoreactive IL-6 was strongly diminished in undifferentiated forms (n = 34) and slightly reduced in well-differentiated carcinoma (n = 65). In agreement with the in vitro results, TGF-alpha expression was significantly increased in neoplastic thyrocytes, as compared to their normal counterpart. The results indicate that, as in the mammary and salivary glands, down-regulation of IL-6 expression may represent a marker of undifferentiated thyroid carcinoma.
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PMID:Reduced expression of interleukin 6 in undifferentiated thyroid carcinoma: in vitro and in vivo studies. 951 26

Human melanoma cell lines derived from early stage primary tumors are particularly sensitive to growth arrest induced by interleukin-6 (IL-6). This response is lost in cell lines derived from advanced lesions, a phenomenon which may contribute to tumor aggressiveness. We sought to determine whether resistance to growth inhibition by IL-6 can be explained by oncogenic alterations in cell cycle regulators or relevant components of intracellular signaling. Our results show that IL-6 treatment of early stage melanoma cell lines caused G1 arrest, which could not be explained by changes in levels of G1 cyclins (D1, E), cdks (cdk4, cdk2) or by loss of cyclin/cdk complex formation. Instead, IL-6 caused a marked induction of the cdk inhibitor p21WAF1/CIP1 in three different IL-6 sensitive cell lines, two of which also showed a marked accumulation of the cdk inhibitor p27Kip1. In contrast, IL-6 failed to induce p21WAF1/CIP1 transcript and did not increase p21WAF1/CIP1 or p27kip1 proteins in any of the resistant lines. In fact, of five IL-6 resistant cell lines, only two expressed detectable levels of p21WAF1/CIP1 mRNA and protein, while in three other lines, p21WAF1/CIP1 was undetectable. IL-6 dependent upregulation of p21WAF1/CIP1 was associated with binding of both STAT3 and STAT1 to the p21WAF1/CIP1 promoter. Surprisingly, however, IL-6 stimulated STAT binding to this promoter in both sensitive and resistant cell lines (with one exception), suggesting that gross deregulation of this event is not the unifying cause of the defect in p21WAF1/CIP1 induction in IL-6 resistant cells. In somatic cell hybrids of IL-6 sensitive and resistant cell lines, the resistant phenotype was dominant and IL-6 failed to induce p21WAF1/CIP1. Thus, our results suggest that in early stage human melanoma cells, IL-6 induced growth inhibition involves induction of p21WAF1/CIP1 which is lost in the course of tumor progression presumably as a result of a dominant oncogenic event.
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PMID:Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. 1002 78

We performed this prospective study to evaluate the correlation of interleukin-6 serum levels with preoperative constitutional symptoms and immunologic abnormalities, and the possible role played by this cytokine in tumor recurrence. Eight patients with atrial myxoma were evaluated at our institution from July 1993 to November 1998. We measured their interleukin-6 serum levels by enzyme-linked immunosorbent assay method preoperatively and 1 and 6 months after surgery. Two of the cases involved recurrent tumor, 1 patient had undergone his 1st surgery at a different institution and died during the 2nd procedure, so his data were incomplete. Preoperatively the whole group of patients had elevated interleukin-6 serum levels. Although patients with a 1st occurrence of tumor demonstrated a positive correlation between interleukin-6 serum level and tumor size, the 2 patients with recurrent tumors appeared to have higher interleukin-6 levels regardless of tumor size. Once the tumor was surgically removed, interleukin-6 levels returned to normal values, and this was associated with regression of clinical manifestations and immunologic features. According to our study, the overproduction of interleukin-6 by cardiac myxomas is responsible for the constitutional symptoms and immunologic abnormalities observed in patients with such tumors and might also play a role as a marker of recurrence. This study also suggests that recurrent cardiac myxomas form a subgroup of cardiac myxomas with a highly intrinsic aggressiveness, as implied by their greater interleukin-6 production despite their smaller size. Further studies are needed to confirm these results.
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PMID:The role of interleukin-6 in cases of cardiac myxoma. Clinical features, immunologic abnormalities, and a possible role in recurrence. 1133 Jul 38

Human malignant non-Hodgkin's lymphomas (NHL) represent a heterogeneous group of neoplasms, which vary in their clinical behavior and pathophysiology. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been shown to play a role in the pathophysiology and clinical aggressiveness of human NHL. In this setting, MMP-9 and TIMP-1 appear to be the most important members of the MMP and TIMP families, and overexpression of both correlates with a poor clinical outcome of patients with NHL. MMP-9 and TIMP-1, however, act through different mechanisms and are produced by different cell types. Expression of both is upregulated by interleukin-6 (IL-6), a cytokine that is known as one of the factors involved in the pathophysiology of human NHL. In this review we summarize the complex regulation of MMP and TIMP expression in human NHL and propose a mechanism by which MMP-9, TIMP-1 and IL-6 may influence the biology of these tumors.
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PMID:Matrix metalloproteinases and their tissue inhibitors - expression, role and regulation in human malignant non-Hodgkin's lymphomas. 1134 32

Giant cell tumor of bone (GCT) is a neoplasm characterized by the presence of large numbers of multinucleated osteoclast-like giant cells, together with mononuclear spindle-shaped cells. Although GCT can be considered a benign lesion, it may exhibit a high biological aggressiveness, which is often associated with enhanced osteolytic properties and development of lung metastasis. By selecting different groups of GCT patients, including patients without evidence of relapse after a median follow-up of 114 months and patients who recurred with lung metastasis, this study focused on the analysis of the expression at clinical onset and in the metastasis of a series of markers involved either in bone resorption modulation or in the metastatic process. By using immunohistochemistry, we analyzed the expression of interleukin-6 (IL-6), a cytokine stimulating bone resorption that has been demonstrated to be released by GCT cells. The expression of factors of the urokinase-type plasminogen activation system, including the urokinase-type plasminogen activator (u-PA) and the plasminogen activator inhibitor type 1 (PAI-1), which have been described to be frequently implicated in the process of degradation of the extracellular matrix during the metastatic process, were also analyzed. Finally, since the action of plasminogen activators is facilitated by the presence of specific receptors on cell surfaces, the analysis included also the u-PA receptor (u-PAR). Our results showed that all these proteins were variably either expressed or overexpressed both in primary tumors and lung metastasis. However, both the level of expression and the incidence of overexpression were higher in primary GCT that relapsed and in lung metastasis compared to primary tumors from disease-free patients, suggesting a possible association of these proteins with a higher biologic aggressiveness of GCT cells. The parallel analysis of a group of primary tumors and of their respective lung metastasis demonstrated that the enhanced expression of one or more of these proteins may confer a selective advantage to GCT cells in terms of systemic invasiveness. Therefore, the evaluation of the expression levels of these proteins at the time of diagnosis may be taken into consideration for a classification of GCT into categories characterized by a different risk to relapse.
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PMID:Identification of markers of possible prognostic value in 57 giant cell tumors of bone. 1257 71

c-Src is a proto-oncogene, belonging to the nonreceptor protein kinases family, which plays a prominent role in carcinogenesis. In this study, we tested the hypothesis that c-Src could promote breast cancer metastasis acting on several cell types and that pharmacological disruption of its kinase activity could be beneficial for the treatment of metastases. Female BALB/c-nu/nu mice were subjected to intracardiac injection of the human breast cancer cells MDA-MB-231 (MDA-231), which induced prominent bone and visceral metastases. These were pharmacologically reduced by treatment with the c-Src inhibitor [7-{4-[2-(2-methoxy-ethylamino-ethoxy]-phenyl}-5-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine] CGP76030 (100 mg/kg/day p.o.), resulting in decreased morbidity and lethality. Metastases were more severe in mice injected with MDA-231 cells stably transfected with wild-type c-Src (MDA-231-SrcWT), whereas transfection in injected cells of a c-Src kinase-dead dominant-negative construct (MDA-231-SrcDN) resulted in reduced morbidity, lethality, and incidence of metastases similar to the mice treated with the inhibitor. An analogous beneficial effect of c-Src inhibition was observed in subcutaneous and intratibial implanted tumors. In vitro, c-Src suppression reduced MDA-231 cell aggressiveness. It also impaired osteoclast bone resorption both directly and by reducing expression by osteoblasts of the osteoclastogenic cytokines interleukin-1beta and interleukin-6, whereas parathyroid hormone-related peptide was not implicated. c-Src was also modestly but consistently involved in the enhancement of endothelial cell proliferation in vitro and angiogenesis in vivo. In conclusion, we propose that c-Src disruption affects the metastatic process and thus is a therapeutic target for the treatment of breast cancer.
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PMID:Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. 1662 50

Deregulated growth and blocks in differentiation collaborate in the multistage process of leukemogenesis. Previously, we have shown that ectopic expression of the zinc finger transcription factor Egr-1 in M1 myeloblastic leukemia cells promotes terminal differentiation with interleukin-6 (IL-6). In addition, we have shown that deregulated expression of the oncogene E2F-1 blocks the myeloid terminal differentiation program, resulting in proliferation of immature cells in the presence of IL-6. Here it is shown that the positive regulator of differentiation Egr-1 abrogates the E2F-1-driven block in myeloid terminal differentiation. The M1E2F-1/Egr-1 cells underwent G(0)/G(1) arrest and functional macrophage maturation following treatment with IL-6. Furthermore, Egr-1 diminished the aggressiveness of M1E2F-1 leukemias and abrogated the leukemic potential of IL-6-treated M1E2F-1 cells. Previously, we reported that Egr-1 abrogated the block in terminal myeloid differentiation imparted by deregulated c-myc, which blocks differentiation at a later stage than E2F-1, resulting in cells that have the characteristics of functionally mature macrophages that did not undergo G(0)/G(1) arrest. Taken together, this work extends and highlights the tumor suppressor role of Egr-1, with Egr-1 behaving as a tumor suppressor against two oncogenes, each blocking myeloid differentiation by a different mechanism. These findings suggest that Egr-1 and/or Egr-1 target genes may be useful tools to treat or suppress oncogene-driven hematological malignancies.
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PMID:Egr-1 abrogates the E2F-1 block in terminal myeloid differentiation and suppresses leukemia. 1759 39

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.
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PMID:Obesity, metabolic syndrome, and prostate cancer. 1826 78


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