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)

By using an AtT20 cell line transfected with complementary DNA for preproTRH, we have identified the proTRH polyeptide precursor [26 kilodaltons (kDa)] and shown that this molecule gives rise to the proTRH derived sequences as determined by pulse-chase and trypsinization studies. The predicted proTRH precursor composed of 231 amino acids with 5 copies of a TRH progenitor sequence (Gln-His-Pro-Gly) and 7 other cryptic peptides was demonstrated by: 1) Western Blot analysis of an AtT20 cell extract with anti-pCC10 antibodies (an antibody that recognizes the intact prohormone as well as some intermediate products of processing); 2) Immunoprecipitation of the radiolabelled 26 kDa protein with anti-pCC10 followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis; 3) Gel filtration chromatography of the radiolabeled 26 kDa extracted from SDS-PAGE. 4) RIA with anti-pCC10 antiserum against peptides extracted from adult rat hypothalamus and olfactory lobe after SDS-PAGE. 5) Trypsinization of the proTRH precursor which generated the proTRH cryptic peptides preproTRH25-50 (pYE27) and preproTRH53-74 (pFT22). These moieties were also produced during trypsinization of intermediate products of processing. By means of pulse-chase studies, the 26 kDa polypeptide was shown to be the biosynthetic precursor to all the proTRH derived cryptic peptides. Cleavage at two positions in the center of the molecule (Lys107-Arg108 and Lys152-Arg153) generated two moieties of 16.5 and 15 kDa. The 15 kDa N-terminal fragment is later cleaved to a 6 kDa peptide that includes the proTRH derived peptides, pYE27, pFT22, and pEH24. The carboxy-terminal 16.5 kDa fragment of the prohormone is processed to a 9.6 kDa fragment which contains the proTRH derived peptide pST10 (preproTRH160-169) and a fragment of 5.4 kDa that may be the C-terminal peptide preproTRH208-255 recognized by antisera pAC12 and pYE17. In further processing, the 9.6 kDa molecule is cleaved to produce a 5.4 kDa peptide from either sequences 115-169 or 160-199.
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PMID:Identification of the thyrotropin-releasing hormone-prohormone and its posttranslational processing in a transfected AtT20 tumoral cell line. 844 Jan 87

Rat interleukin-6 (IL-6) cDNA, coding for an important inflammation- and immune-regulatory polypeptide cytokine, was cloned into the novel expression vector pH6EX3 which directs the synthesis of inserted genes as a fusion protein with histidine hexapeptide (HH). The resultant vector (pRIL6.992) was shown to produce significant amounts of recombinant rat IL-6 fusion protein with HH at its N-terminus in various strains of Escherichia coli. The expression of the HH-IL-6 fusion protein was demonstrated to be under the control of the tac promoter and could be induced by IPTG. This protein was isolated from bacterial inclusion bodies and purified to homogeneity in a one-step procedure by affinity chromatography using a nickel-chelating column. The HH-IL-6 fusion protein isolated in this manner was biologically active as determined by hepatocyte stimulation and B9 hybridoma growth assays. Further, this activity was neutralized with a polyclonal antiserum raised against rat IL-6 protein generated in a novel fashion from rabbits infected with a recombinant human type-5 adenovirus vector expressing rat IL-6 protein (Ad5E3rIL6). The recombinant HH-IL-6 protein was then used to boost Ad5E3rIL6-immunized rabbits. This resulting antiserum was shown to neutralize recombinant and natural rat and murine IL-6 bioactivity in vitro and was useful in Western blot analysis and immunohistochemistry of rat IL-6.
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PMID:Vector-derived expression of recombinant rat interleukin-6. 886 Jun 52

Unlike monoclonal antibodies, clinical application of bispecific antibodies has so far lagged behind because of difficult, low-yield production techniques as well as considerable toxicity attributed to bispecific antibody preparations containing immunoglobulin-Fc parts and anti-CD3 homodimers. These difficulties were overcome by recombinant generation of a bispecific single-chain antibody (bscAb) joining two single-chain Fv fragments via a five-amino-acid glycine-serine linker. The anti-CD3 specificity directed against human T cells was combined with another specificity against the epithelial 17-1A antigen. The following domain arrangement was critical in this individual case to obtain a fully functional bscAb: VL17-1A-VH17-1A-VHCD3-VLCD3. The bscAb was expressed in chinese hamster ovary cells with a yield of 15 mg/l culture supernatant whereas numerous attempts to obtain a functional protein expression in Escherichia coli failed. The low-molecular-mass bispecific construct (60 kDa) could easily be purified by its C-terminal histidine tail. The antigen-binding properties are indistinguishable from those of the corresponding univalent single-chain Fv fragments as shown by enzyme immunoassay and flow cytometry. We could show that the bscAb, which lacks Fc parts and anti-CD3 homodimers is highly cytotoxic for 17-1A positive tumor cells in nanomolar concentrations and in the presence of human T cells. Most remarkable, it does not stimulate T lymphocyte proliferation in the absence of tumor cells and, moreover, does not induce CD25 up-regulation and the secretion of potentially toxic lymphokines such as tumor necrosis factor alpha, interleukin-6 and interferon gamma. Maximal cytotoxicity (51Cr release) was achieved without notable costimulation and was not further enhanced by adding costimulatory signals such as those delivered by anti-CD28 antibodies. CD8+ as well as CD4+ T cell subpopulations were recruited to exert cytotoxicity against tumor cells with different kinetics. CD8+ cells induced high 51Cr release within 4 h while CD4+ cells required a 20-h incubation. The systemic application of the 17-1A/CD3-bscAb could be a major improvement in therapy against disseminated micrometastatic tumor cells. A prospective, randomized clinical trial showing that an anti-17-1A monoclonal antibody could prolong survival of colorectal cancer patients after 5 and 7 years, warrants an assessment of the clinical efficacy of this bscAb exhibiting a 1000-fold higher specific cytotoxicity against tumor cells in vitro.
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PMID:Construction and biological activity of a recombinant bispecific single-chain antibody designed for therapy of minimal residual colorectal cancer. 943 72

We describe a patient with a malignant carcinoid tumor who presented with severe, intractable hypercalcemia that would not respond to conventional therapy with fluids and pamidronate. His plasma concentrations of parathyroid-hormone-related peptide (PTHrP) and interleukin-6 (IL-6) were elevated. The patient was treated with subcutaneous injections of octreotide with a good response, resulting in normocalcemia. Plasma PTHrP and IL-6 fell with the octreotide but remained elevated above the upper limit of normal. We conclude that although rare, hypercalcemia may be associated with carcinoid tumors and may be mediated through the secretion of cytokines and or PTHrP. Treatment with octreotide may be effective in treating hypercalcemia in such patients.
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PMID:Intractable hypercalcemia due to a metastatic carcinoid secreting parathyroid hormone-related peptide and interleukin-6: response to octreotide. 1048 14

Photodynamic therapy (PDT), utilizing a photosensitizer and visible light, causes localized oxidative damage. With the mitochondrial photosensitizer Pc 4, PDT induces apoptosis, yet its molecular targets are not known. Here, the anti-apoptotic protein Bcl-2 is shown to be highly sensitive to PDT, as judged on Western blots by the disappearance of anti-Bcl-2-reactive material from the position of the native 26 kDa protein. The loss of Bcl-2 was PDT dose dependent and was observed for both endogenous and overexpressed Bcl-2 in several cell lines, immediately after PDT, and with chilled cells. It was accompanied by a trace of a 23-kDa cleavage product as well as high-molecular weight products that may result from photochemical crosslinking. PDT-induced Bcl-2 loss occurred in MCF-7 cells that do not express caspase-3 or in the presence of protease inhibitors, but was prevented, along with the induction of apoptosis, by the singlet oxygen scavenger L-histidine. Loss of FLAG-Bcl-2 was observed with both anti-FLAG and anti-Bcl-2 antibodies, indicating loss of native protein rather than simple BCL-2-epitope destruction. Photochemical damage was not observed in Bcl-x(L), Bax, Bad, the voltage-dependent anion channel, or the adenine nucleotide translocator. Therefore, Bcl-2 is one target of PDT with Pc 4, and PDT damage to Bcl-2 contributes to its efficient induction of apoptosis.
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PMID:Photochemical destruction of the Bcl-2 oncoprotein during photodynamic therapy with the phthalocyanine photosensitizer Pc 4. 1142 92

Suppression subtractive hybridization technology was used to identify differentially expressed genes in spleens of chickens that had been treated with the synthetic immune modifier S-28463. One induced chicken gene encoded a protein with about 35% sequence identity to human interleukin-6 (IL-6). It consists of 241 amino acids including a putative N-terminal signal peptide of 47 residues. Bacterially expressed chicken IL-6 (ChIL-6) carrying a histidine tag in place of the signal peptide was biologically active: it induced proliferation of the IL-6-dependent murine hybridoma cell line 7TD1. The concentration of ChIL-6 required for half-maximal proliferative response was approximately 60 pg.mL-1. When injected intravenously into adult chickens, purified recombinant ChIL-6 induced an increase in serum corticosterone levels. Supernatants of chicken LMH and monkey COS-7 cells transiently transfected with a ChIL-6 expression construct induced proliferation of 7TD1 cells, demonstrating that recombinant ChIL-6 from eukaryotic cells is also active.
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PMID:Chicken interleukin-6. cDNA structure and biological properties. 1148 13

Antisense oligodeoxynucleotides (ODNs) can inhibit gene expression in a specific manner. However, several studies described problems with cerebral ODN application. Here, we investigated the immune effects (interleukin-6 (IL-6) release, cell invasion into cerebrospinal fluid (CSF) and brain parenchyma) of 'non-sense' randomized ODNs with different counterions (NH(4)(+), Na(+)) and modifications (with or without thioat-backbone) which were administered intracerebroventricularly for 48 h using osmotic mini-pumps in a rat model. All animals receiving ODNs showed increased IL-6 levels in the CSF as well as cell invasion into the CSF and brain parenchyma (P<0.05). However, the use of thioat-backbone and ammonium as the counterion induced the highest IL-6 levels (7210+/-1696 pg/ml, P<0.05) and the highest cell numbers in the CSF (31.6+/-15.5x10(5)/ml, P<0.05) as well as brain parenchyma (268.1+/-143.2 HIS-48+ cells/mm(2), P<0.01; and 31.3+/-10.7 OX-6+cells/mm(2), P<0.05) compared with the other groups.
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PMID:Oligodeoxynucleotides induce brain inflammation in rats when infused intracerebroventricularly. 1195 55

Castleman disease (CD) is a rare heterogeneous lymphoproliferative disease characterized by clinical symptoms due to an excess of interleukin-6 (IL-6) or IL-6-like activity. We describe the first case of CD associated with acute myelogenous leukemia (AML). A 55-year-old man presented with skin rash on his face and multiple cervical lymphadenopathy. The results of examination of his lymph node biopsy specimen led to a diagnosis of CD. The symptoms resolved after the administration of prednisolone. Three years after the onset of CD, the patient's white blood cell count had increased to 63.4 x 10(9)/L. His bone marrow aspirate showed that approximately 80% of cells were leukemic, including well-differentiated monocytic cells A diagnosis of AML M5b was made. The patient died of invasive pulmonary aspergillosis after chemotherapy.
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PMID:Acute myelogenous leukemia M5b developed during clinical remission of Castleman disease. 1273 71

Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) is the third most common cause of community-acquired pneumonia and is probably involved in the development of certain chronic inflammatory diseases, including atherosclerosis and adult-onset asthma. Histamine, synthesized by histidine decarboxylase (HDC) from L-histidine, plays an essential role in allergic and inflammatory processes and in cell differentiation. The effect of C. pneumoniae infection on the expression of HDC has not been examined. In the present study, normal Balb/c mice and HDC knockouts, and control mice with a CD1 background were infected intranasally with C. pneumoniae. On days 1, 3, 7, 16 and 31 after infection, the normal Balb/c mice were sacrificed and divided into three groups. In the homogenized lungs of the first group, C. pneumoniae titres were determined and demonstrated peak levels on day 7. HDC production was revealed by a Western blot assay throughout the observation period of 1-16 days, and cytokine concentrations were determined by ELISA. The interleukin-3 (IL-3) and interleukin-6 (IL-6) levels were highest on day 1 and on days 1-3, respectively; the interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels reached the maximum on day 7, but the quantity of IL-4 was still three times higher than that in the control group 16 days after infection. The lungs of the mice in the second group were processed for the in situ demonstration of HDC activity, while the lungs in the third group were stained for C. pneumoniae antigen. The HDC activity was increased predominantly in the bronchial epithelial cells, while C. pneumoniae antigens were expressed especially in the interstitial macrophages. The HDC knockout mice exhibited a higher survival rate after C. pneumoniae infection than did the control mice. These results point to a strong association between local histamine production and other inflammatory mediators and are novel in demonstrating the role of histamine in the pathomechanism of C. pneumoniae infections.
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PMID:Chlamydophila (Chlamydia) pneumoniae induces histidine decarboxylase production in the mouse lung. 1455 83

The lipopeptide FSL-1 [S-(2,3-bispalmitoyloxypropyl)-Cys-Gly-Asp-Pro-Lys-His-Pro-Lys-Ser-Phe, Pam(2)CGDPKHPKSF] synthesized on the basis of the N-terminal structure of a Mycoplasma salivarium lipoprotein capable of activating normal human gingival fibroblasts to induce the cell surface expression of ICAM-1 revealed an activity to induce production of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-8. FSL-1 also activated macrophages to produce tumor necrosis factor alpha as the Mycoplasma fermentans-derived lipopeptide MALP-2 (Pam(2)CGNNDESNISFKEK), a potent macrophage-activating lipopeptide, did. The level of the activity of FSL-1 was higher than that of MALP-2. This result suggests that the difference in the amino acid sequence of the peptide portion affects the activity because the framework structure other than the amino acid sequence of the former is the same as that of the latter. To determine minimal structural requirements for the activity of FSL-1, the diacylglyceryl Cys and the peptide portions were examined for this activity. Both portions did not reveal the activity. A single amino acid substitution from Phe to Arg and a fatty acid substitution from palmitic acid to stearic acid drastically reduced the activity. Similar results were obtained in measuring the NF-kappaB reporter activity of FSL-1 to human embryonic kidney 293 cells transfected with Toll-like receptor 2 and 6, together with a NF-kappaB-dependent luciferase reporter plasmid. These results suggest that both the diacylglyceryl and the peptide portions of FSL-1 are indispensable for the expression of biological activities and for the recognition by Toll-like receptors 2 and 6 and that the recognition of FSL-1 by Toll-like receptors 2 and 6 appears to be hydrophobic.
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PMID:Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6. 1497 73


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