Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:021712 (IL-6)
 58,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we report on novel immunoregulatory functions lately attributed to fibroblasts, namely participation in cellular immune responses in connective tissues, by generation of pro-inflammatory cytokines and by presenting antigens to proliferating T cells. In order to execute immunoregulatory functions, the fibroblast has to be activated by signals abundant at inflammatory sites, i.e., cytokines and bacterial products. It was demonstrated that such immune-activated fibroblasts are able to generate a variety of cytokines such as interleukin-1 (IL-1), IL-6, colony stimulating factors (CSFs) as well as prostaglandins. The array of cytokines generated by immune-activated fibroblasts is determined by the stimulant and is controlled at multiple regulatory levels, such as transcription, translation, post-translational modifications, compartmentalization within the producing cell as well as the timing of expression. Some oncogene-transformed fibroblastoid cells lines were shown to constitutively generate IL-1 (and not IL-1 beta), as evidenced by the continuous expression of specific mRNA and biological activity of the cytokine, associated to the cell membrane or located in the cytosol. When these IL-2 producing cell lines were injected into mice, they failed to generate established tumors or regressed following initial growth, possibly due to mounting the host anti-tumor specific immune responses in which cytotoxic lymphocytes (CTLs) predominate. In contrast, IL-1 non-producing tumor cell lines induced progressive tumors which ultimately killed the animals. However, IL-1 non-producing fibroblastoid cell lines shifted from an in vivo progressive to a regressive phenotype, following immune activation of the malignant cells in vitro with cytokines/LPS. Similarly, primary immune-activated fibroblasts also induced tumor regression, mediated by anti-tumor specific immune responses, when the fibroblasts were injected into the vicinity of the tumor. Thus, the importance of activated stromal cells on tumor development was emphasized. This situation is relevant to the development of malignancies, as tumor growth is often accompanied by a local inflammatory response. Thus, the induction of IL-1 and other pro-inflammatory cytokines expression by the malignant cells or by stromal cells, in the vicinity of the tumor, might be efficient for tumor eradication. These findings should serve as a basis for development of novel immunotherapeutical strategies for the eradication of solid tumors.
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PMID:IL-1 and pro-inflammatory cytokines produced by primary and transformed fibroblasts abrogate the tumorigenic potential of fibrosarcomas. 142 19

Ascitic fluid from human ovarian cancer patients often contains a large number of leukocytes along with tumor cells. Some of the recent evidence suggests that the ascitic fluid contains factors capable of inducing the growth of ovarian cancer cells in vitro and in vivo. While these factors have not yet been completely characterized, growth factors secreted by the tumor cells could influence the tumor growth by paracrine and autocrine mechanisms. Earlier, we reported that ovarian epithelial cancer cells produce macrophage colony-stimulating factor. It appears that these tumor cells produce more than one cytokine. Identifying the various products secreted by the tumor cells would provide valuable information needed to understand the biology of ovarian cancer. In the present study, evidence is provided for the first time that five different human ovarian epithelial tumor cell lines and tumor cells isolated from the ascitic fluid of four cancer patients express interleukin (IL) 1 alpha and beta genes constitutively. Production of the lymphokine was determined by analyzing the cellular RNA for IL-1-related transcripts and by immunological assays. Ovarian cancer cells also secrete another pleiotropic cytokine, IL-6, constitutively. In many systems, IL-1 induces the expression of the IL-6 gene. To determine whether the basal levels of IL-6 production are dependent on the endogenous IL-1, neutralization studies were carried out. Addition of antibodies to IL-1 did not decrease the levels of IL-6 secreted by the cancer cell lines. These results suggest that multiple cytokines are produced by ovarian cancer cells and that the endogenous IL-1 may not be directly involved in the regulation of IL-6 gene expression in these cells.
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PMID:Human ovarian epithelial cancer cells cultures in vitro express both interleukin 1 alpha and beta genes. 155 28

Cytokines are important regulatory proteins controlling growth and differentiation of normal and malignant glial cells. Astrocytes and microglial cells produce and respond to many of the same cytokines employed by cells of the immune system. The authors have analyzed 15 histologically confirmed malignant glial neoplasms for the presence of infiltrating lymphocytes, macrophages, cytokines, and other immunoregulatory molecules using a panel of specific monoclonal and polyclonal antibodies on frozen-tissue sections. All neoplasms showed focal T-cell infiltration with CD8 cells predominating. Infiltration of activated macrophages (positive for CD11c, class II, and interleukin-2 receptor) was marked in all tumors. Within the neoplasm, tumor necrosis factor-alpha (TNF-alpha)- and interleukin (IL)-6-positive macrophages were prominent in five cases, while the tumor cells themselves were only weakly positive. In the other 10 cases, the numerous infiltrating macrophages were only rarely immunoreactive for TNF-alpha or IL-6. Transforming growth factor-beta (TGF-beta) immunoreactivity was most prominent in those tumors with little TNF-alpha-positive macrophage infiltration, although intratumoral variability was present. This study suggests that, in malignant gliomas, the cytokines TNF-alpha and IL-6, although weakly present in neoplastic cells, are most prominent in infiltrating macrophages and in those regions of the tumors that show little immunoreactivity for TGF-beta. The important interactions among neoplastic, reactive glial, and inflammatory cells, which regulate tumor growth, are likely to be in part mediated through these molecules.
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PMID:Cytokines and immunoregulatory molecules in malignant glial neoplasms. 162 16

Myeloma is one of the interleukin (IL)-6-related diseases to which abnormal expression of IL-6 has been reported to be linked. We examined the in vivo inhibitory effect of anti-human IL-6 receptor (IL-6R) antibody on human myeloma cell growth in mice. SCID mice were subcutaneously inoculated with solid tumor of the myeloma cell line S6B45 in which human IL-6 was acting as an autocrine growth factor. Ten intraperitoneal administrations of 100 micrograms of the anti-human IL-6R antibody PM1 at 48-h intervals strongly inhibited the growth of S6B45 cells when the administration started 24 h after tumor inoculation. The tumor growth inhibition in vivo was also observed by administration of the anti-human IL-6 antibody MH166 using the same procedure as for PM1. The inhibitory effect of PM1 was not significant when the administration started 5 or more days after tumor inoculation. This work indicates that anti-human IL-6R antibody, as well as anti-human IL-6 antibody inhibits human myeloma growth in vivo, and provides an animal model for testing the therapeutic value of agents such as antibodies to human IL-6, IL-6R and gp130, an IL-6R-associated signal transducer, in the treatment of human myelomas.
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PMID:Anti-human interleukin-6 receptor antibody inhibits human myeloma growth in vivo. 163 1

The aim of this study was to evaluate to what extent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 may explain the development of experimental cancer cachexia. For this purpose, C57BL/6J mice bearing a transplantable low differentiated rapidly growing tumor were passively immunized every other day with rabbit or rat neutralizing immunoglobulins against either TNF-alpha (anti-TNF) or against an interleukin 1 receptor (anti-IL-1r). Anti-IL-1r in itself had no agonistic effect to the type I, T-cell/fibroblast IL-receptor. Tumor-bearing mice receiving either preimmune antiserum or nonimmune rat hybridoma IgG served as controls. Anti-TNF and anti-IL-1r inhibited tumor growth significantly, as measured by a lower wet and dry tumor weight at the end of 11 days of antiserum treatment (P less than 0.05). The acute phase response in tumor-bearing animals, measured as an increase in liver weight, hepatic RNA content, and increases in plasma concentrations of circulating IL-6, serum amyloid P, transferrin, complement (C3), and a decrease in plasma albumin, were unaffected by the specific antiserum treatments. Food intake, which declined significantly in pre/nonimmune injected tumor-bearing controls, was significantly improved in tumor-bearing animals immunized against TNF-alpha or the IL-1r. Whole body lipid content showed a trend to improvement in specifically immunized animals (P less than 0.07). The effects on whole body fat-free dry weight were insignificant, although numerically higher in specifically immunized tumor-bearing animals. The combination of anti-TNF and anti-IL-1r antiserum had no additive effects compared to single antiserum treatment suggesting that the two antibody treatments acted through a common mechanism. Cultured tumor cells, established from growing tumors, were sensitive to anti-TNF and anti-IL-1r, which both reduced tumor growth in vitro. This inhibitory effect by the antiserum could in part be reversed by the addition of recombinant IL-1 alpha and TNF alpha. We conclude that both TNF and IL-1 are involved in tumor growth and thus the progression of cancer cachexia. It seems as if the role of TNF and IL-1 was to promote tumor growth rather than restrict tumor growth in the present model. In this sense both TNF and IL-1 may act as tumor growth factors.
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PMID:Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. 170 40

IL-6 is a major tumor growth factor in human multiple myeloma. Myeloma cell lines, which have the same phenotypic characteristics and Ig gene rearrangements as the original fresh myeloma cells and whose growth is strictly dependent on exogenous IL-6 similar to fresh myeloma cells, have been reproducibly established. We show here that IFN-alpha stimulated the growth of five of six of these human myeloma cell lines by inducing an autocrine production of IL-6 in myeloma cells. Indeed, IFN-alpha induced IL-6 mRNA accumulation and IL-6 production in myeloma cells and the IFN-alpha-induced growth of these cells was inhibited by anti-IL-6 mAb. Moreover, IFN-alpha made possible the rapid emergence of autonomously growing myeloma cell sublines, which produced IL-6 as an autocrine growth factor. As IFN-alpha has a potential therapeutical interest for multiple myeloma, the present study opens up new directions for studying its effects on the myeloma clone in vivo.
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PMID:IFN-alpha induces autocrine production of IL-6 in myeloma cell lines. 175 8

The detection of an increasing number of cytokines and the demonstration of autocrine and paracrine mechanisms perpetuating tumor growth prompted the investigation of the expression of the cytokines IL-2, IL-3, IL-4, IL-5, IL-6, IFN gamma, Tac, and GMCSF in primary lymph-node biopsies of patients with peripheral T-cell lymphoma (n = 11), Hodgkin's disease (n = 13), and large-cell anaplastic lymphoma (n = 6) by means of Northern blot analysis and in situ hybridization (ISH); 15 of 28 cases had IL-6 message, predominantly in cases of Hodgkin's disease (HD) and large-cell anaplastic lymphomas (LCAL). Interferon gamma was found in about 50% of the cases among all entities. Other cytokine expression was rare except two cases of HD with high amounts of IL-4 mRNA. These results indicate that large amounts of growth factor transcripts are present in a variety of malignant lymphomas. The meaning of this expression is still unclear. It may be a loss of physiologic regulation within the cytokine network which may thus influence neoplastic cell growth as some cases have a quantity of cytokine expression which is similar or even above that of stimulated T cells. ISH demonstrates in individual cases that the expression is at least in part due to malignant cells.
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PMID:Cytokine expression in T-cell lymphomas and Hodgkin's disease. Its possible implication in autocrine or paracrine production as a potential basis for neoplastic growth. 195 32

The protein-bound polysaccharide extracted from a fungus, PSK, has been used as a biological response modifier in the treatment of cancer patients in Japan for over ten years. Although the antitumor mechanism of PSK is not fully understood, host-mediated antitumor activity has been claimed to play a significant role. The administration of PSK to tumor-bearing rodents inhibited tumor growth and modulated immune responses. To clarify the potential immunomodulating activities of PSK, we examined the direct effect of PSK on cytokine gene expression and production in human peripheral blood mononuclear cells (PBMC) in vitro. As determined by Northern blotting, PSK was a potent inducer of gene expression for IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor (TNF-alpha) and monocyte chemotactic and activating factor (MCAF), but not for IL-2 and lymphotoxin (LT). Expression of mRNA occurred at 1-3 hr in a dose dependent manner using from 5-400 micrograms/ml of PSK. Furthermore, these cytokines were also produced in response to PSK as detected by ELISA, RIA or bioassays. We speculate that these cytokines may mediate immunoenhancing actions of PSK in vivo.
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PMID:Induction of gene expression and production of immunomodulating cytokines by PSK in human peripheral blood mononuclear cells. 209 Aug 74

Beside their therapeutic effects, cytokines are involved in pathologies such as IL-6 in myeloma tumor growth and bone resorption, BCGF in the proliferation of hairy cell leukemic cells, IL-2 in the capillary leak syndrome. For biotherapy to develop, it is necessary to understand both the beneficial and the deletorious effects of cytokines.
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PMID:Pathophysiology of cytokines. 220 18

Weight-stable mice bearing a syngeneic, methylcholanthrene-induced, rapidly growing tumor lost approximately 22% of their lean tissue, became significantly hypoalbuminemic and had a marked increase in serum amyloid P concentrations during progressive tumor growth. Tumors from cachectic mice were producing both TNF-alpha and IL-1 alpha in vivo as documented by the presence of TNF-alpha and IL-1 alpha mRNA and immune-reactive protein for IL-1 alpha. Only spleens from tumor-bearing mice had statistically significantly elevated quantities of IL-1 mRNA. In general, alterations in tissue concentrations of IL-1 mRNA in tumor-bearing animals agreed qualitatively with those found in endotoxin-stimulated, non-tumor-bearing control mice. However, endotoxin-stimulated mice had significantly elevated tissue concentrations of TNF mRNA in spleen and livers, while TNF mRNA levels were not significantly increased in any host tissues. Cytokine mRNA levels in tumor tissue were not higher than those found constitutively in various tissues from non-tumor-bearing control animals. Plasma from tumor-bearing mice and endotoxin-stimulated controls contained high levels of IL-6 but low (endotoxin-stim.) or no measurable levels (tumor-bearing) of either IL-1 or TNF. When tumor cells from cachectic mice were placed into long-term cell culture, immune reactive TNF-alpha and IL-1 alpha were produced, but IL-6 bioactivity ws not produced in measurable amounts.
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PMID:Tumor necrosis factor-alpha and interleukin-1 alpha production in cachectic, tumor-bearing mice. 222 17


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