Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “IL6”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1992

A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6.

Using a DNA probe from the DNA-binding portion of the NF-IL6 gene and an antibody against the DNA-binding domain of NF-IL6, we isolated a gene homologous to NF-IL6 in the DNA-binding and leucine zipper domains. This intronless gene, termed NF-IL6 beta encodes a 269-amino acid protein with a potential leucine zipper structure, and the gene product can bind to the CCAAT homology as well as the viral enhancer core sequence, as in the cases of NF-IL6 and C/EBP. This gene is expressed at an undetectable or a minor level in normal tissues but is induced by lipopolysaccharide or inflammatory cytokines, as in the case of NF-IL6. NF-IL6 beta easily forms a heterodimer with NF-IL6 in vitro and the heterodimeric complex binds to the same DNA sequence as the respective homodimers. When examined by transient luciferase assays, NF-IL6 beta is consistently a stronger transactivator than NF-IL6. Furthermore, NF-IL6 beta shows a synergistic transcriptional effect with NF-IL6. These data suggest that NF-IL6 beta is an important transcriptional activator in addition to NF-IL6 in regulation of the genes involved in the immune and inflammatory responses.

Amino Acid Sequence↗
PubMed1991

Reciprocal expression of NF-IL6 and C/EBP in hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expression.

The initial phase of inflammation is accompanied by dramatic changes in the concentrations of certain plasma proteins. Interleukin-6 (IL-6) is an important inducer of these acute phase proteins at the transcriptional level. The recently cloned nuclear factor NF-IL6, a potent trans-acting regulator of IL-6 gene expression, has a region that is highly homologous to the liver-specific transcriptional factor C/EBP. Both factors recognize the same nucleotide sequence. In this study the recombinant NF-IL6 was shown to interact with the IL-6-responsive elements (IL-6REs) identified in the promoter region of several acute phase protein genes whose activity increases during the acute phase reaction. Furthermore, in competition experiments, formation of all the DNA-protein complexes by the IL-6RE and IL-6-treated hepatoma cell extracts was specifically decreased by adding either the 14-bp NF-IL6 binding motif identified in the IL-6 promoter or the antibody against the recombinant NF-IL6. NF-IL6 was expressed at a minor level in mouse liver, but was dramatically induced after stimulation with IL-6. In contrast, the amount of C/EBP mRNA decreased considerably after IL-6 stimulation. These results indicate that the NF-IL6 that regulated IL-6 expression was also involved in regulation of expression of the acute phase protein genes. The ability of NF-IL6 to replace C/EBP may explain the positive and negative acute phase responses induced by IL-6.

Acute-Phase Proteins↗
PubMed1991

The Interleukin-6-dependent DNA-binding protein gene (transcription factor 5: TCF5) maps to human chromosome 20 and rat chromosome 3, the IL6 receptor locus (IL6R) to human chromosome 1 and rat chromosome 2, and the rat IL6 gene to rat chromosome 4.

Using two panels of somatic cell hybrids segregating either human or rat chromosomes, the gene encoding the interleukin-6-dependent DNA-binding protein, also called liver activator protein (designated transcription factor 5: TCF5), was assigned to human chromosome 20 and to rat chromosome 3. The TCF5 gene might be identical with the NF-IL6 gene. The locus encoding the IL6 receptor gene (IL6R) was localized to human chromosome 1 and rat chromosome 2. An IL6R-like (IL6RL) locus was also assigned to human chromosome 9. In addition, the rat interleukin-6 (IL6) gene was assigned to rat chromosome 4. These mapping data allow one to extend comparison between the rat, mouse, and human gene maps.

Animals↗
PubMed1990

Cytotoxicity of IL6-PE40 and derivatives on tumor cells expressing a range of interleukin 6 receptor levels.

The chimeric toxin IL6-PE40, which is composed of interleukin 6 (IL6) fused to a mutant form of Pseudomonas exotoxin (PE) devoid of its native cell recognition domain, can kill myeloma and hepatoma cells which express high levels of IL6 receptors. To enhance the usefulness of IL6-PE40 on potential target cells, we have attempted to develop more potent IL6-PE derivatives. We have developed nine new IL6-PE derivatives and assessed their cytotoxicity on human myeloma cells. Two of these new forms, IL6-domain II-PE40 and IL6-PE664Glu were more toxic to myeloma cells bearing IL6 receptors than was IL6-PE40. These two chimeric toxins were compared with IL6-PE40 for cytotoxicity toward a variety of tumor cell lines. We found that most tumor cell lines which are sensitive to IL6-PE40 are more sensitive to IL6-domain II-PE40 and IL6-PE664Glu. Cells with as few as 200-600 IL6 receptors/cell could be killed. The specificity of these chimeric toxins was shown through competition with recombinant IL6. Toxicity studies in mice demonstrated that the two new molecules had an LD50 of 10-20 micrograms/mouse. This compares to an IL6-PE40 LD50 of 20 micrograms/mouse. The new IL6-toxins could be detected in the serum up to 8 h after intraperitoneal administration with a peak at 1 h. These data suggest that IL6-domain II-PE40 and IL6-PE664Glu may be more useful than IL6-PE40 in killing IL6 receptor-bearing tumor cells in animals.

ADP Ribose Transferases↗
PubMed1990

Cell-specific toxicity of a chimeric protein composed of interleukin-6 and Pseudomonas exotoxin (IL6-PE40) on tumor cells.

IL6-PE40 is a chimeric toxin composed of human interleukin-6 (IL6) linked by a peptide bond to PE40, a form of Pseudomonas exotoxin (PE) devoid of its cell recognition domain. To identify cancer cell lines with high numbers of IL6 receptors and to assess the usefulness of IL6-PE40 as a possible anticancer agent, we evaluated the toxicity of IL6-PE40 on a variety of tumor cell lines and demonstrated that certain human myeloma and hepatoma cell lines were particularly sensitive. IL6 binding to selected hepatoma and myeloma cell lines were determined by using [125I]IL6. IL6 receptor mRNA levels were measured by polymerase chain reactions. When comparisons were made among different hepatoma cell lines, the sensitivity to IL6-PE40 correlated with the number of IL6 receptors. However, the hepatoma line PLC/PRF/5, which contains 2,300 IL6 receptors, was more sensitive to IL6-PE40 (amount of protein required to inhibit protein synthesis by 50% was 5 ng/ml) than both the myeloma cell lines U266 and H929 (for both cell lines, the 50% inhibitory dose was 8 ng/ml), which contain 15,500 and 16,500 IL6 receptors, respectively. RNA analysis confirmed that the sensitivity of these cells to IL6-PE40 and the amount of IL6 receptor RNA detected did not correlate. These data suggest that factors in addition to the number of IL6-binding sites contribute to the sensitivity of cells to IL6-PE40.

ADP Ribose Transferases↗
PubMed1992

IL-6 and NF-IL6 in acute-phase response and viral infection.

NF-IL6 was originally identified as a DNA-binding protein responsible for IL-1-stimulated IL-6 induction. Direct cloning of NF-IL6 revealed its homology with C/EBP. C/EBP is expressed in liver and adipose tissues and is supposed to regulate several hepatocyte- and adipocyte-specific genes. In contrast, NF-IL6 is suppressed in normal tissues, but is rapidly and drastically induced by LPS or inflammatory cytokines such as IL-1, TNF, and IL-6. NF-IL6 can also bind to the regulatory region of various genes including IL-8, G-CSF, IL-1 and immunoglobulin genes. Furthermore, NF-IL6 is shown to be identical to IL-6DBP, a DNA-binding protein responsible for IL-6-mediated induction in acute-phase proteins, demonstrating that NF-IL6 is responsible for the genes regulated by IL-6. These results indicate that NF-IL6 may be a pleiotropic mediator of many inducible genes involved in acute, immune, and inflammatory responses, like NFkB. In this regard, it is noteworthy that both an NF-IL6 binding site and an NFkB binding site are present in the inducible genes such as IL-6, IL-8, and several acute-phase genes. On the other hand, accumulating evidence has revealed that overproduction of IL-6 may be responsible for the pathogenesis and/or several symptoms of a variety of diseases, including autoimmune diseases, malignancies, and viral diseases. At present, the molecular mechanisms of abnormal expression of the IL-6 gene are not known. Recently it has become evident that interplays between viral proteins and cellular proteins play an important role in viral oncogenesis and infection. The fact that NF-IL6 binds to the enhancer core sequences of various viruses strongly suggests a possible relationship of virus infection and IL-6 expression. In fact some evidence (Mahe et al. 1991, Spergel et al. 1992) indicates that NF-IL6 may interact with viral gene enhancers or viral products, although there are no definite data about the involvement of NF-IL6 in viral pathogenesis. Future studies will be required to clarify whether or not the interplay between NF-IL6 and viral infection is responsible for deregulation of the IL-6 gene.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1.

We investigated the regulation of IL6 biological activity, de novo synthesis, and mRNA levels in adult vascular endothelial cells (EC) by bacterial endotoxin or inflammatory cytokines. Cells incubated without stimulus released scant IL6 activity. IFN gamma, IL2, or PDGF did not augment IL6 release from EC. LPS, lipid A, and TNF increased IL6 release modestly (5 to 20-fold), while recombinant IL1s (rIL1s) stimulated this process 100 to 400-fold. Differential release of IL6 from EC treated with LPS or rIL1 continued for at least 144 hr. Exposure to LPS or rIL1 caused EC to synthesize IL6 de novo. EC secreted the newly synthesized IL6 into the supernatant, rather than retaining it within or bound to cells. EC accumulated IL6 mRNA after 3 hr of exposure to rIL1. However, we could only detect IL6 message in cells incubated with LPS under "superinduction" conditions with cycloheximide, consistent with lower levels of IL6 biological activity in response to LPS compared to IL1 stimulation. We propose that local production of IL6 by vascular EC, which comprise the barrier between tissues and the blood, may influence regional immune and inflammatory responses.

Antigen-Antibody Reactions↗
PubMed1992

NF-IL6, a member of the C/EBP family, regulates E1A-responsive promoters in the absence of E1A.

A cDNA encoding NF-IL6, an interleukin-6 (IL-6)-regulated human nuclear factor of the C/EBP family, is demonstrated to complement the transactivation function of E1A. The endogenous NF-IL6 level varies according to cell type and correlates positively with an IL-6-regulated cellular E1A-substituting activity that was described recently (J.M. Spergel and S. Chen-Kiang, Proc. Natl. Acad. Sci. USA 88:6472-6476, 1991). When expressed by transfection in cells which contain low levels of NF-IL6 and are incapable of complementing the function of E1A proteins, NF-IL6 also transactivates the E1A-responsive E2ae and E1B promoters, to the same magnitude as E1A. Activation by NF-IL6 is concentration dependent and sequence specific: mutational studies of the E2ae promoter suggest that the promoter-proximal NF-IL6 recognition site functions as a dominant negative regulatory site whereas the promoter-distal NF-IL6 recognition site is positively regulated at low NF-IL6 concentrations and negatively regulated when the NF-IL6 level is high. Consistent with these functions, NF-IL6 alone is sufficient to complement an E1A deletion mutant dl312 in viral infection, when expressed at appropriate concentrations. These results identify NF-IL6 as a sequence-specific cellular nuclear factor which regulates E1A-responsive genes in the absence of E1A.

Adenovirus Early Proteins↗
PubMed1992

[Synergism between transcription factors NF-IL6 and NF-kappa B in IL-6 gene regulation].

NF-IL6 and NF-kappa B are nuclear proteins supposed to play an important role in the regulation of acute-phase protein synthesis and inflammatory response against infection and tissue injury as a host defence mechanism. In addition the promoter region of the interleukin-6 (IL-6) gene has a NF-kappa B binding motif as well as a NF-IL6 binding site. Considering of these facts, we come to investigate that there may be a synergistic effect between NF-IL6 and NF-kappa B in the regulation of IL-6 gene expression. In order to study it, some combinations of expression vectors NF-IL6 cDNA, NF-kappa B (p50/p65) cDNA and reporter plasmid K18-CAT which contains human IL-6 promoter linked to the chloramphenicol acetyltransferase (CAT) gene, were transfected into Jurkat cells and the CAT activities were examined. Co-transfection of NF-IL6 and NF-kappa B (p50/p65) cDNA revealed a dramatic increase of acetylated [14C] chloramphenicol, and its CAT activity reached to 40%. Then, co-transfection of NF-IL6 and NF-kappa B subunit p65 alone showed a high level of CAT activity, too. When 5' deletion mutant reporter plasmid K9-CAT lacking the NF-IL6 binding site was used, co-transfection of NF-IL6 and NF-kappa B (p50/p65) showed low level of CAT activity. These results indicate that there is a synergistic effect between NF-IL6 and NF-kappa B (p50/p65) in IL-6 gene regulation. Among two subunits of NF-kappa B (p50/p65), p65 seems to play an important role rather than p50 does in synergism between NF-IL6 and NF-kappa B. Besides, this synergistic function comes to work only when NF-IL6 binds to its binding site of IL-6 promoter region.

Binding Sites↗
PubMed1989

Recombinant interleukin (IL) 2-induced human B cell differentiation is mediated by autocrine IL6.

The molecular mechanism of the interleukin (IL) 2-induced differentiation of human B cells has been investigated. The experimental results show that Staphylococcus aureus Cowan strain I (SAC) activation alone induces IL6 secretion from B cells. When B cells were activated by SAC, there was an increased transcription of the IL6 mRNA. It reached the peak level by 6 h and rapidly decreased to an undetectable level within 24 h. The IL6 concentration in the culture supernatants reached the peak at 24-48 h and decreased slightly in the following culture periods. Since IL 2 alone could induce IgG secretion, whether exogenous IL6 was added or not, and IL2 did not increase autocrine IL6 synthesis, it appears that IL2 induces the IL6 responsiveness of SAC-activated B cells to differentiate in the later stage of the culture. The addition of polyclonal anti-IL6 antibody inhibited IgG secretion. The antibody still efficiently blocked IgG secretion up to day 5, indicating an important role of autocrine IL6 in the IL2-driven B cell differentiation. However, the saturation dose of anti-IL6 antibody inhibited 50%-70% of IgG secretion, suggesting that IL2-induced B cell differentiation appears to be mediated by other factors besides IL6.

B-Lymphocytes↗
PubMed1992

Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6.

The interleukin 6 (IL-6) promoter is rapidly and transiently activated by other cytokines, including IL-1 and tumour necrosis factor (TNF), as well as by phorbol esters and cyclic AMP agonists. Studies using promoter mutants suggested that an IL-1-responsive element mapped within the -180 to -123 region of the IL-6 promoter. A nuclear factor (NF-IL6) that recognized a unique sequence containing an inverted repeat, ACATTGCACAATCT, was identified within the region. Direct cloning of the human NF-IL6 revealed its similarity to C/EBP, a liver- and adipose tissue-specific transcription factor. C/EBP and NF-IL6 recognize the same nucleotide sequence, but exhibit distinct patterns of expression. NF-IL6 is expressed at a low level in normal tissues, but is rapidly and drastically induced by bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1, TNF and IL-6. Recently, NF-IL6 has been shown to be identical to IL-6DBP, the DNA-binding protein which is responsible for IL-6-mediated induction of several acute-phase proteins. Evidence that NF-IL6 DNA-binding activity is increased after IL-6 stimulation without increased NF-IL6 protein synthesis demonstrates the importance of post-translational modification. There are some results indicating that phosphorylation is involved in transcriptional and binding activities of NF-IL6. Taken together, these findings indicate that NF-IL6 may be an important transcription factor on the signal transduction pathways of IL-1 and IL-6.

Acute-Phase Proteins↗
PubMed1990

A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.

NF-IL6 is a nuclear factor that specifically binds to an IL1-responsive element in the IL-6 gene. In this study the gene encoding NF-IL6 has been cloned by direct screening of a lambda gt11 library using NF-IL6 binding sequence as a ligand. The full-length cDNA encoded a 345 amino acid protein with a potential leucine zipper structure and revealed a high degree of homology to a liver-specific transcriptional factor, C/EBP, at the C-terminal portion. The bacterial fusion protein bound to the CCAAT homology as well as the viral enhancer core sequences as in the case of C/EBP. Recombinant NF-IL6 activated the human IL-6 promoter in a sequence-specific manner. Southern blot analysis demonstrated the high-degree conservation of the NF-IL6 gene through evolution and the existence of several other related genes sharing the DNA-binding domain. NF-IL6 mRNA was normally not expressed, but induced by the stimulation with either LPS, IL-1 or IL-6. Interestingly, NF-IL6 was shown to bind to the regulatory regions for various acute-phase protein genes and several other cytokine genes such as TNF, IL-8 and G-CSF, implying that NF-IL6 has a role in regulation not only for the IL-6 gene but also for several other genes involved in acute-phase reaction, inflammation and hemopoiesis.

Acute-Phase Reaction↗
PubMed1991

Constitutive release of IL6 by human papillomavirus type 16 (HPV16)-harboring keratinocytes: a mechanism augmenting the NK-cell-mediated lysis of HPV-bearing neoplastic cells.

In the present study we demonstrate that the cultured human keratinocyte cell line (SK-v cells) harboring and expressing integrated human papillomavirus type 16 (HPV16) DNA sequences constitutively releases IL6, which is known as a pleiotropic immunoregulatory cytokine of potential antitumor properties. The presence of IL6 activity in SK-v cell-conditioned media (SK-v CM) was demonstrated by tritiated thymidine incorporation into IL6-dependent B9 murine plasmacytoma cells. The effect on B9 cells was specific since it could be inhibited by anti-IL6 neutralizing antibodies but not by a normal control serum. IL6 did not affect SK-v cell growth; however, it significantly augmented NK cell activity of human peripheral blood lymphocytes against both K562 erytholeukemic and SK-v cells as assessed by 51Cr release assay. SK-v CM displayed NK cell-augmenting activity that copurified with IL6 activity in both size exclusion and anion-exchange HPLC. Furthermore, SK-v cell-derived NK cell stimulatory activity could be neutralized with anti-IL6 antibodies. These results suggest that HPV-harboring neoplastic cells can release IL6 which may indirectly mediate tumor death by augmentation of NK cell activity.

Cytotoxicity, Immunologic↗
PubMed1992

Effects of IL6 on B cells in mucosal immune response and inflammation.

Freshly isolated surface IgA+ (sIgA+) B cells from human gut-associated lymphoreticular tissues (GALT), e.g. the appendix, express high levels of IL6 receptor (IL6R) and respond to IL6 with significant increases in the number of IgA-secreting cells. On the other hand, neither sIgM+ nor sIgG+ B cells from appendix express IL6R. When the effect of IL6 on IgA subclass antibody synthesis was examined, the numbers of both IgA1- and IgA2-producing cells were increased upon incubation of GALT B cells with IL6; however, 60-70% of IgA-secreting cells were IgA2 subclass. Aberrant local production of IL6 can contribute to increased B-cell responses that occur in mucosal inflammation such as gingiva of patients with adult periodontitis (AP). When gingival mononuclear cells (GMC) isolated from AP patients were cultured without any stimulus, GMC spontaneously produced biologically active IL6 which induced peripheral blood mononuclear cells (PBMC) from the same patients to become IgG- and IgA-producing cells. Further, mRNA extracted from GMC possessed high message for IL6. When the expression of IL6R was compared between GMC and PBMC isolated from AP patients, IL6R-bearing cells were only seen in the former population. Thus, a high production of IL6, which have the ability to regulate later stages of IL6R+ B-cell development and to induce them to become Ig-secreting plasma cells and to support plasmacytoma growth, are important immunopathological elements for the induction of the increased B-cell response region in inflamed mucosal tissues.

Appendix↗
PubMed1990

Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts.

We have examined the effect of dexamethasone (DM) and cortisol on the production of interleukin (IL)6 from the murine macrophage cell line RAW264.9, human monocytes, human endothelial cells and the human fibroblast cell line FS4. In RAW264.9 cells DM in the concentration range 10(-9) M to 10(-6) M inhibited the lipopolysaccharide (LPS)-induced production of IL6 by 10% to 90%. Cortisol had a similar effect, but was about 25 times less potent than DM. Also, when 10(-6) M of DM was added to the cultures after addition of LPS, it completely inhibited the residual 24-h production of IL6. Corresponding to the effect on IL6 production, DM (10(-6) M) reduced the mRNA levels for IL6 in the RAW264.9 cells. The glucocorticoid analogue RU 486 competes with DM and cortisol for the glucocorticoid receptor and reversed the inhibitory effect of DM, demonstrating that DM exerts its effect via the glucocorticoid receptor. DM also had an inhibitory effect on LPS-stimulated IL6 production in freshly isolated human monocytes, and on IL 1-stimulated IL6 production in human endothelial cells and FS4 fibroblasts. These results demonstrate that DM via a receptor-mediated mechanism inhibits IL6 production at the transcriptional level, and this may contribute to the anti-inflammatory and immunosuppressive effect of glucocorticoids.

Animals↗
PubMed1992

IL6 and acute phase plasma proteins in peritoneal fluid of women with endometriosis.

Several authors have documented signs of chronic inflammation in the pelvis of women with endometriosis. We investigated the possible involvement of interleukin 6 (IL6), an important regulator of inflammation and immunity, in minimal and mild endometriosis by measuring levels of IL6 and proteins (alpha 1-acid glycoprotein, alpha 1-antitrypsin, alpha 2-HS glycoprotein and albumin) the synthesis of which is regulated by IL6, in peritoneal fluid (PF) from infertile women with histologically confirmed endometriosis (stage I and II; n = 28) and from endometriosis-free fertile (n = 14) and infertile women (n = 13). Spontaneous and LPS-induced IL6 secretion by cultured PF macrophages from women with endometriosis (n = 12) and without endometriosis (n = 9) were also studied. No significant differences were observed in the concentrations of the four proteins studied. Immunoreactive IL6 was detected in all three groups, with no significant differences. In contrast, significantly higher levels of IL6 were released by both unstimulated (P = 0.01) and LPS-stimulated (P = 0.006) peritoneal macrophages from the women with endometriosis. We conclude that local IL6 synthesis by activated macrophages may play a role in the endometriosis process.

Acute-Phase Proteins↗