title: Cyclotides Suppress Human T-Lymphocyte Proliferation by an Interleukin 2-Dependent Mechanism.
abstract: 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 IL-2 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.
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria ; Center for Complementary Medicine, Department of Environmental Health Sciences, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Gründemann
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thell
authors.forename: Karin
authors.initials: K
authors.lastname: Lengen
authors.forename: Manuel
authors.initials: M
authors.lastname: Garcia-Käufer
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
authors.forename: Roman
authors.initials: R
authors.lastname: Huber
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Christian W
authors.initials: CW
authors.lastname: Gruber
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D047169:Cyclotides / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D019666:Rubiaceae / Q000737:chemistry; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects
chemical_list: D047169:Cyclotides; D007376:Interleukin-2; C091930:kalata B1
keywords: cyclotide; cytokine; immunosuppression; lymphocytes; peptide; plant; proliferation