Cyclotides Suppress Human T-Lymphocyte Proliferation by an Interleukin 2-Dependent Mechanism
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{"title"=>"Cyclotides Suppress Human T-Lymphocyte Proliferation by an Interleukin 2-Dependent Mechanism", "type"=>"journal", "authors"=>[{"first_name"=>"Carsten", "last_name"=>"Gründemann", "scopus_author_id"=>"11839626900"}, {"first_name"=>"Kathrin", "last_name"=>"Thell", "scopus_author_id"=>"55776338300"}, {"first_name"=>"Karin", "last_name"=>"Lengen", "scopus_author_id"=>"55776395800"}, {"first_name"=>"Manuel", "last_name"=>"Garcia-Käufer", "scopus_author_id"=>"54580820200"}, {"first_name"=>"Yen Hua", "last_name"=>"Huang", "scopus_author_id"=>"56980702600"}, {"first_name"=>"Roman", "last_name"=>"Huber", "scopus_author_id"=>"19034687100"}, {"first_name"=>"David J.", "last_name"=>"Craik", "scopus_author_id"=>"7102228054"}, {"first_name"=>"Gernot", "last_name"=>"Schabbauer", "scopus_author_id"=>"6506325625"}, {"first_name"=>"Christian W.", "last_name"=>"Gruber", "scopus_author_id"=>"14046875500"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"23840803", "sgr"=>"84879484015", "doi"=>"10.1371/journal.pone.0068016", "scopus"=>"2-s2.0-84879484015", "pui"=>"369200406", "issn"=>"19326203"}, "keywords"=>["cyclotide", "cytokine", "immunosuppression", "lymphocytes", "peptide", "plant", "proliferation"], "id"=>"098f9bcf-93e8-35e0-aa0a-a89876641d7a", "abstract"=>"<p>Cyclotides are a diverse and abundant group of ribosomally synthesized plant peptides containing a unique cyclic cystine-knotted topology that confers them with remarkable stability. Kalata B1, a representative member of this family of mini-proteins, has been found to inhibit the proliferation of human peripheral blood mononuclear cells. Analysis of T-cell proliferation upon treatment with chemically synthesized kalata B1 mutants revealed a region comprising inter-cysteine loops 1 and 2 of the cyclotide framework to be important for biological activity. Cytokine signaling analysis using an ‘active’ kalata B1 mutant [T20K], and the reference drug cyclosporin A (CsA) demonstrated that treatment of activated T-lymphocytes with these compounds decreased the expression of the interleukin-2 (IL-2) surface receptor as well as IL-2 cytokine secretion and <italic>IL-2</italic> gene expression, whereas the ‘inactive’ kalata B1 mutant [V10K] did not cause any effects. The anti-proliferative activity of [T20K] kalata B1 was antagonized by addition of exogenous IL-2. Furthermore, treatment with [T20K] kalata B1 led to an initial reduction of the effector function, as indicated by the reduced IFN-γ and TNF-α production, but the levels of both cytokines stabilized over time and returned to their normal levels. On the other hand, the degranulation activity remained reduced. This indicated that cyclotides interfere with T-cell polyfunctionality and arrest the proliferation of immune-competent cells through inhibiting IL-2 biology at more than one site. The results open new avenues to utilize native and synthetically-optimized cyclotides for applications in immune-related disorders and as immunosuppressant peptides.</p>", "link"=>"http://www.mendeley.com/research/cyclotides-suppress-human-tlymphocyte-proliferation-interleukin-2dependent-mechanism", "reader_count"=>20, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Medicine and Dentistry"=>2, "Agricultural and Biological Sciences"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>4, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1101359"], "description"=>"<p>The structure of kalata B1 is shown in cartoon form (<b>A</b>). The six conserved cysteines are labeled with Roman numerals and the cystine knot disulfide connectivity (C<sub>I</sub>-C<sub>IV</sub>, C<sub>II</sub>-C<sub>V</sub> and C<sub>III</sub>-C<sub>VI</sub>) is indicated. The amino acid sequence and the loops of the kalata B1 backbone are shown in C. The positions of the mutations are indicated by red arrows in the cartoon and are highlighted with red letters in the sequence. The α-H chemical shift comparison of kalata B1 (full circles), [V10K] kalata B1 (open triangles) and [T20K] kalata B1 (open squares) is shown for all residues starting from residue G1 (<b>B</b>). The amino acid sequence (with mutations highlighted in red) and a surface representation of kalata B1 (PDB code: 1NB1) is shown in (<b>C</b>). The structure is using a hydrophobicity scale according to Eisenberg et al. [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068016#B53\" target=\"_blank\">53</a>] to illustrate the amphiphilic nature of these peptides. Typical hydrophilic regions of cyclotides are in loops 2 and 3, whereas the hydrophobic patch is found on the opposite site in loops 5 and 6. Mutated amino acids, e.g., in [V10K] and [T20K] kalata B1 were modeled using the PyMol mutation wizard and have been shown in red color in the enlarged window. All Figure representations were prepared using PyMol.</p>", "links"=>[], "tags"=>["kalata", "b1", "cyclotide"], "article_id"=>731720, "categories"=>["Biological Sciences"], "users"=>["Carsten Gründemann", "Kathrin Thell", "Karin Lengen", "Manuel Garcia-Käufer", "Yen-Hua Huang", "Roman Huber", "David J. Craik", "Gernot Schabbauer", "Christian W. Gruber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068016.g001", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_of_kalata_B1_and_cyclotide_mutants_/731720", "title"=>"Structure of kalata B1 and cyclotide mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 06:55:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1101360"], "description"=>"<p>The influence of medium (ctrl), CsA (0.8 µM) or different concentrations of the kalata B1 cyclotide mutants [T8K], [V10A], [V10K], [G18K], [T20K] and [N29K]\n\t\t\t\t\t\t\t(1.8-14 μM) on proliferation of activated primary lymphocytes was measured by cell division analysis using CFSE-based flow cytometry on day three post stimulation. Data are presented as mean ± SD of four (three for [T20K] kalata B1) independent donors and experiments. Corresponding IC<sub>50</sub> values have been presented in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068016#tab1\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["cyclotide", "mutants", "proliferation", "activated"], "article_id"=>731721, "categories"=>["Biological Sciences"], "users"=>["Carsten Gründemann", "Kathrin Thell", "Karin Lengen", "Manuel Garcia-Käufer", "Yen-Hua Huang", "Roman Huber", "David J. Craik", "Gernot Schabbauer", "Christian W. Gruber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068016.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_cyclotide_mutants_on_cell_proliferation_of_primary_activated_human_lymphocytes_/731721", "title"=>"Effects of cyclotide mutants on cell proliferation of primary activated human lymphocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 06:55:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1101361"], "description"=>"<p>For IL-2 receptor expression studies, lymphocytes were treated with CsA or cyclotides (4 µM each) and were cultivated in the presence of media (Ø) or activation stimuli alone (ctrl). At 24 h (<b>A</b>) or 36 h (<b>B</b>) after cultivation, cells were surface-stained with anti-human CD25 mAbs and were analyzed by flow cytometry. For IL-2 secretion analysis, lymphocytes (<b>C</b>) or purified T-cells (<b>D</b>) were restimulated with PMA (50 ng/mL) and ionomycin (500 ng/mL) for 6 h after 24 h of cultivation. Afterwards, the amount of IL-2 was individually measured in the supernatant by using ELISA-based techniques. The <i>il-2</i> gene expression of lymphocytes was analyzed by quantitative RT-PCR (<b>E</b>). The data were normalized to the cycle threshold value of the internal housekeeping gene <i>18s rRNA</i> and the relative mRNA level in the untreated stimulated group was used as calibrator. Data are expressed as mean ± SD of independent donors and experiments as indicated. For IL-2 receptor analysis representative data were additional depicted as dot plots. The asterisks represent significant differences (*<i>P</i> <0.05, **<i>P</i> <0.01, ***<i>P</i> <0.001) of treated cells in comparison to ctrl (PHA-L stimulated cells alone).</p>", "links"=>[], "tags"=>["cyclotide", "mutants", "il-2", "activated", "lymphocytes", "purified"], "article_id"=>731722, "categories"=>["Biological Sciences"], "users"=>["Carsten Gründemann", "Kathrin Thell", "Karin Lengen", "Manuel Garcia-Käufer", "Yen-Hua Huang", "Roman Huber", "David J. Craik", "Gernot Schabbauer", "Christian W. Gruber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068016.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_cyclotide_mutants_on_IL_2_biology_of_primary_activated_human_lymphocytes_and_purified_T_cells_/731722", "title"=>"Effects of cyclotide mutants on IL-2 biology of primary activated human lymphocytes and purified T-cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 06:55:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1101363"], "description"=>"<p>CFSE-labeled primary human lymphocytes were pretreated with CsA or cyclotides (4 µM each) and were activated using PHA-L (10 µg/mL), followed by washing off the cyclotides and activation stimuli. Furthermore, the cells were cultured without (<b>A</b> and <b>B</b>) or in the presence of exogenous recombinant human IL-2 (<b>C</b> and <b>D</b>). The proliferation capacity of the cells was analyzed at day three by flow cytometry. Representative data are presented in dot plots (<b>A</b> and <b>B</b>) and summary of three independent experiments were presented as mean ± SD (<b>B</b> and <b>D</b>). The values in dot plots represents the amount of proliferated lymphocytes on which the quantification to control is based. The asterisks represent significant differences of treated cells in comparison to ctrl (PHA-L stimulated cells alone) (*<i>P</i> <0.05, **<i>P</i> <0.01, ***<i>P</i> <0.001).</p>", "links"=>[], "tags"=>["exogenous", "il-2", "proliferation", "cyclotide-treated"], "article_id"=>731724, "categories"=>["Biological Sciences"], "users"=>["Carsten Gründemann", "Kathrin Thell", "Karin Lengen", "Manuel Garcia-Käufer", "Yen-Hua Huang", "Roman Huber", "David J. Craik", "Gernot Schabbauer", "Christian W. Gruber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068016.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_exogenous_IL_2_on_proliferation_capacity_of_cyclotide_treated_lymphocytes_/731724", "title"=>"Effects of exogenous IL-2 on proliferation capacity of cyclotide-treated lymphocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 06:55:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1101364"], "description"=>"<p>Purified lymphocytes were preincubated with CsA or cyclotides\n\t\t\t\t\t\t\t(4 µM each), then stimulated with PHA-L (10 µg/mL) and exposed to a re-stimulation impulse with PMA and ionomycin for 6 h before analysis of effector functions, expressed as amounts of IFN-γ (24 h: <b>A</b>; 36 h: <b>B</b>), TNF-α (24 h: <b>C</b>; 36 h: <b>D</b>) or degranulation capacity (<b>E</b>). The amount of IFN-γ and TNF-α was measured in the supernatant of cultured cells using an ELISA-based method for early time points, or intracellular cytokine detection flow cytometric analysis for late time points. The degranulation capacity was detected by using classical CD107a assay. Data of three independent experiments were presented as mean ± SD. The asterisks represent significant differences of treated cells in comparison to ctrl or PHA-L stimulated cells alone (*<i>P</i> <0.05, **<i>P</i> <0.01, ***<i>P</i> <0.001).</p>", "links"=>[], "tags"=>["cyclotide", "mutants", "effector", "activated"], "article_id"=>731725, "categories"=>["Biological Sciences"], "users"=>["Carsten Gründemann", "Kathrin Thell", "Karin Lengen", "Manuel Garcia-Käufer", "Yen-Hua Huang", "Roman Huber", "David J. Craik", "Gernot Schabbauer", "Christian W. Gruber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068016.g005", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Influence_of_cyclotide_mutants_on_effector_function_of_primary_activated_human_lymphocytes_/731725", "title"=>"Influence of cyclotide mutants on effector function of primary activated human lymphocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 06:55:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1101366", "https://ndownloader.figshare.com/files/1101368", "https://ndownloader.figshare.com/files/1101369", "https://ndownloader.figshare.com/files/1101372"], "description"=>"<div><p>Cyclotides are a diverse and abundant group of ribosomally synthesized plant peptides containing a unique cyclic cystine-knotted topology that confers them with remarkable stability. Kalata B1, a representative member of this family of mini-proteins, has been found to inhibit the proliferation of human peripheral blood mononuclear cells. Analysis of T-cell proliferation upon treatment with chemically synthesized kalata B1 mutants revealed a region comprising inter-cysteine loops 1 and 2 of the cyclotide framework to be important for biological activity. Cytokine signaling analysis using an ‘active’ kalata B1 mutant [T20K], and the reference drug cyclosporin A (CsA) demonstrated that treatment of activated T-lymphocytes with these compounds decreased the expression of the interleukin-2 (IL-2) surface receptor as well as IL-2 cytokine secretion and <i>IL-2</i> gene expression, whereas the ‘inactive’ kalata B1 mutant [V10K] did not cause any effects. The anti-proliferative activity of [T20K] kalata B1 was antagonized by addition of exogenous IL-2. Furthermore, treatment with [T20K] kalata B1 led to an initial reduction of the effector function, as indicated by the reduced IFN-γ and TNF-α production, but the levels of both cytokines stabilized over time and returned to their normal levels. On the other hand, the degranulation activity remained reduced. This indicated that cyclotides interfere with T-cell polyfunctionality and arrest the proliferation of immune-competent cells through inhibiting IL-2 biology at more than one site. The results open new avenues to utilize native and synthetically-optimized cyclotides for applications in immune-related disorders and as immunosuppressant peptides.</p> </div>", "links"=>[], "tags"=>["suppress", "t-lymphocyte", "proliferation", "interleukin", "2-dependent"], "article_id"=>731727, "categories"=>["Biological Sciences"], "users"=>["Carsten Gründemann", "Kathrin Thell", "Karin Lengen", "Manuel Garcia-Käufer", "Yen-Hua Huang", "Roman Huber", "David J. Craik", "Gernot Schabbauer", "Christian W. Gruber"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0068016.s001", "https://dx.doi.org/10.1371/journal.pone.0068016.s002", "https://dx.doi.org/10.1371/journal.pone.0068016.s003", "https://dx.doi.org/10.1371/journal.pone.0068016.s004"], "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cyclotides_Suppress_Human_T_Lymphocyte_Proliferation_by_an_Interleukin_2_Dependent_Mechanism_/731727", "title"=>"Cyclotides Suppress Human T-Lymphocyte Proliferation by an Interleukin 2-Dependent Mechanism", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-06-26 06:55:35"}

PMC Usage Stats | Further Information

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Relative Metric

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